Non-Odontogenic Tumors of the Jaws

Etiology

Osteosarcoma

The true etiology of osteosarcoma is unknown. Most research analyses the pathogenesis of osteosarcoma of the long bones rather than being specific to the jaws. The relevance of this distinction is the variation in characteristics and clinical behavior between the two. Osteosarcoma of the jaw has a later onset, is more commonly low-grade, has a reduced risk of metastasis, and better overall prognosis.

Tumor suppressor genes p53 and RB1 mutations are thought to be involved in tumor initiation.[21] An environment of rapid bond growth is thought to increase risk, accounting for the increased incidence of osteosarcoma in Paget disease. Additionally, environmental factors such as ionizing radiation and chromic oxide have increased the risk of osteosarcoma.[22][23]

Fibrous Dysplasia

Fibrous dysplasia is caused by a genetic mutation in GNAS 1, leading to defective bone maturation during embryogenesis. This mutation occurs at different points in embryogenesis for each individual, altering the population size of daughter cells carrying the mutation. This accounts for the heterogeneity seen and is a form of somatic mosaicism. It is felt that earlier mutations lead to conditions like McCune-Albright syndrome and later monostotic fibrous dysplasia.

Central Giant Cell Granuloma

It was once thought that central giant cell granuloma represented a local reparative response to traumatic or inflammatory intramedullary hemorrhage.[24][25] This is no longer widely believed, and instead, they are thought to represent neoplastic changes.[26] Evidence has shown that deregulation of the cell cycle may contribute to pathogenesis.[27]

Osteoma

The cause of osteoma is unknown. Multiple theories exist, defining them as either development abnormalities, neoplastic events, or a reactionary response. Most cited within the literature is that of a reaction to trauma or infection, with subsequent subperiosteal edema, bleeding and muscle traction thought to trigger uninhibited bone growth. Evidence to support abnormal muscle traction is their development in proximity to the muscular attachment on the lower border of the mandible.[28][29]

Osteochondroma

There are many theories as to the development of osteochondromas. Some believe they occur due to epiphyseal cartilage herniation. Alternatively, due to their common formation at the insertion of the lateral pterygoid, some suggest that periosteal stress triggers the cartilaginous potential of accumulated embryonic cells in the region of tendon insertion.[30] The most commonly cited theory is that pluripotent cells within the periosteum undergo metaplastic changes and endochondral ossification.[16]

Osteoblastoma

With the large degree of debate on the categorization and natural history of osteoblastoma, it is not surprising that etiology is poorly understood. Some have stated that trauma and abnormal local response to injury are involved, but little is truly understood.[31]

Epidemiology

Osteosarcoma

Osteosarcoma of the jaw is seen later than osteosarcoma of long bones, with an average onset in the third to fourth decade. It is seen equally in both genders. Osteosarcoma of the jaws represented only 6% of all osteosarcomas.[23][32]

Fibrous Dysplasia

This is a rare disease encountered in young individuals, with few cases occurring after 20 years. There appears to be no sex predilection.[33]

Central Giant Cell Granuloma

Population incidence is thought to be 0.0001%.[34] The peak age is between 5 and 15 years, and it rarely develops after 30 years.[26] It most commonly affects females, at a ratio of 2 to 1.[10]

Osteoma

Osteoma of the jaw is rare, with an incidence of 0.01 to 0.04%.[13] There is no predilection of age. Some state thereof being a predominance in males. However, it is also reported as no bias and female bias within the literature, suggesting that any predilection present is not strongly so.[14][15]

Osteochondroma

Osteochondroma can occur at any age, more commonly over 20 years.[30] Compared to long bone osteochondromas, those in the facial skeleton develop at older ages, with the mean between 20 and 40 years. Males are affected at a ratio of 2 to 1.

Osteoblastoma

Osteoblastoma of the jaw is seen more commonly in males at a ratio of 6 to 4. The age of onset is broad-ranging, 5 to 60 years.[35] The peak onset is 20 years, with the more aggressive subset seen in adolescents or young adults.[18]

Histopathology

Osteosarcoma

Osteosarcoma is of mesenchymal origin and exhibits proliferation of osteoblastic precursors, which produce osteoid and immature bone. Neoplastic cells will show anaplasia, filling of marrows space, and erosion of trabecular bone. They can be histologically classified depending on the extracellular matrix cells produced: osteoblastic, chondroblastic, and fibroblastic. The osteoblastic subtype is most commonly observed in the jaws.[36] The precise histology can be variable and can cause diagnostic difficulty, and often multiple biopsies are taken before a diagnosis can be made.

Fibrous Dysplasia

It must be noted that fibrous dysplasia is indistinct from ossifying fibroma histologically and, therefore, may only be commented on as a ‘fibro-osseous lesion.’[37] Disorganized, loose, fibrous tissues replace normal bone without evidence of osteoblastic cells at bony spicules. Instead, stromal fibroblast-like cells take on the osteoblastic role, producing the bony matrix.

Central Giant Cell Granuloma

Histology shows these lesions to be localized, lobulated, and have osteolytic proliferations. Vascular connective tissue is observed, with a patchy distribution of multinucleated giant cells in the surrounding stoma. Extravasated erythrocytes and hemosiderin deposits are frequently seen, highlighting multifocal hemorrhage.[25][26][27] Occasionally trabecular woven bone is observed.[10] These giant cells carry osteoclastic receptors, bind to osteoclast-specific monoclonal antibodies, and respond to calcitonin. They are therefore considered to be precursors to or represent osteoclasts.[38] More aggressive versions have been shown to have more numerous, larger giant cells with a greater surface area density.[27]

Osteoma

Histology can divide osteomas into compact or cancellous. Compact osteomas, also known as ‘ivory’ osteomas, will exhibit a mature, dense lamellar with minimal fibrous marrow tissue. Cancellous osteomas, however, will exhibit trabecular bone with intervening fibrous fatty marrow and a peripheral cortex.[15]

Osteochondroma

Histology shows a bony lesion with a hyaline and fibrous cartilaginous coverage, commonly described as a cap. At the cartilage-to-bone interface, endochondral ossification is commonly observed.[30]

Osteoblastoma

The histology of osteoblastoma causes a significant degree of debate, specifically in distinguishing it from low-grade osteosarcoma.[18] It is characterized by a proliferation of large epithelioid osteoblasts and osteoid, surrounded by a highly vascularized fibrous connective stroma.[31] Various amount of calcification is present, and osteoclasts are often observable.[19] Osteosarcoma is distinguishable by its increased pleomorphism, high mitotic activity, and giant cells.[31]

History and Physical

Osteosarcoma

Osteosarcomas of the jaw present with swelling, as opposed to the pain often seen in osteosarcoma of the axial skeleton.[32] Paraesthesia, mobile teeth, and nasal obstruction may also be observed. It is not uncommon for patients to attribute their symptoms to recent dental treatment.[39] Patient misattribution of symptoms and the difficulties in obtaining a diagnosis can lead to delayed diagnosis of osteosarcoma.

Fibrous Dysplasia

Fibrous dysplasia presents as painless, asymmetric bony expansion in children and adolescents. Its onset tends to occur with periods of high skeletal growth and will often stabilize as skeletal maturity is obtained.[33] Differing functional consequences will occur depending on the bones affected. Malocclusion is often seen with the displacement of teeth, splaying of roots, and crowding. The maxillary sinus may ossify, but more concern focuses on the commonly co-affected zygoma, sphenoid bone, frontal bone, and orbit. Significant fibrous dysplastic changes in this region can lead to blindness.[40]

Central Giant Cell Granuloma

Central giant cell granuloma may be indolent, causing a painless bony swelling.[24] When aggressive, it causes a rapidly enlarging painful swelling, displacing teeth, resorbing roots, and the cortical plate of the alveolar ridge. Intra-orally, a blue, brown discoloration may be seen due to thinning of the cortical plate and overlying mucosal. Clinical expansion occurs over a period of a fortnight to a couple of months.[26]

Osteoma

Osteomas are slow-growing lesions that can remain asymptomatic for years. This means that they can be incidental findings on imaging. Depending on their location and size, they can cause distortion of form and function. They can lead to trismus, malocclusion, and occasionally pain; aesthetically, they can cause facial asymmetry and prominent swellings.[15]

Osteochondroma

As these lesions commonly occur in the mandibular condyle or coronoid process, symptoms are related to temporomandibular joint dysfunction.[16] With time they will alter occlusion, leading to an ipsilateral open bite, crossbite, facial asymmetry, and, if reaching a certain size on the coronoid process, trismus.[41] There have also been reports of posterosuperior growth of condylar osteochondromas leading to external auditory canal stenosis and hearing loss. Due to their slow growth and condylar adaptation, clinical symptoms may be milder than anticipated.[42]

Osteoblastoma

Often patients will show minimal symptoms of osteoblastoma, and swelling with fluctuating, dull-pain related to bone expansion may be experienced. The duration of symptoms varies from months to years.[19] Osteoid osteomas are clinically distinguished by painful swellings (<2 cm diameter), which are worse at night and relieved by salicylates. This differing clinical presentation has made people feel they represent a different entity. Some state them to represent an early phase of osteoblastoma, where there is a higher degree of inflammation due to the central nidus activity. As they expand and outgrow their sclerotic border, the inflammatory response lessens, as does the pain experienced and response to salicylates.[43]

Osteoblastomas are classically felt to have limited growth potential, not exceeding 4cm. The exception to this is an aggressive osteoblastoma seen in younger individuals.[31] It is thought that rapid expansion and increased size may be due to a higher degree of osteoblastic activity in children and young adults. As previously stated, these lead to increased local destruction and high recurrence rates.[19][20]

Evaluation

Osteosarcoma

The features seen on plain film radiographs vary depending on the destructive nature of the tumor and the degree of remineralization. Often, a lesion with irregular, poorly defined margins is observed. Several classical signs may be noted. They are not pathognomonic for osteosarcoma and are not always present. Codman’s triangle is an effect caused by the elevation of the periosteum over the lesion in a tent-like manner. The classical ‘sun-ray’ appearance describes the invasion of the periosteum by thin spicules of bony tumors in an outward direction. Garrington’s sign describes widening of the periodontal ligament and inferior alveolar nerve canal.[36]

More precise imaging should be undertaken, ideally with magnetic resonance imaging (MRI), to assess the extent and invasion of the lesion, specifically looking at marrow involvement and relation to surrounding structures; this will allow for tumor staging.[39]

Biopsy through the center of the lesion must be obtained to get an accurate tissue diagnosis. Osteosarcoma can be a difficult histological diagnosis, and occasionally repeated biopsies are required. Staging scans are undertaken specifically to assess thoracic metastasis, most commonly through a computerized tomography (CT) of the chest.

Fibrous Dysplasia

On radiographs, fibrous dysplasia is a poorly defined lesion that merges into surrounding bone. It has a classical ‘ground glass’ appearance. It may begin as a lucent lesion and become more sclerotic over time. On CT imaging, there is a buccolingual expansion and thus thinning of the cortical plate. There is also a characteristic 3-dimensional displacement of the inferior alveolar nerve canal and loss of the lamina dura around affected teeth.

Central Giant Cell Granuloma

When assessing central giant cell granulomas, it is important to exclude any underlying systemic diagnosis. Hyperparathyroidism will lead to brown tumors, which will occur as multiple osteoclastic giant cell tumors. Cherubism will cause bilateral lesions in the mandible of young children. Bloods work assessing bone profile and PTH levels is important, and family history might highlight potential cherubism.[10][24]

Radiographic assessment is not pathognomonic and may vary. It will show a radiolucent lesion, which may be small around the root of a tooth or large, involving most of the jaw, resorbing the cortical plate and adjacent teeth. For small lesions, plain radiographs may suffice. For large, aggressively destructive lesions, 3-dimensional CT imaging will provide a more complete picture of the bony destruction.[11]

Osteoma

Osteoma may be incidental findings on imaging. However, in the case of clinical detection, assessment with initial radiographs will show a well-defined radio-opacity.[13] Further detailed analysis with CT should be considered. This will show a commonly well-circumscribed, broad-based, or pedunculated mass in more detail.[15] CT scanning will allow assessment of surrounding structures and a 3-dimensional view of the lesion, important when planning operative management.[12][13]

Osteochondroma

Plain film radiograph of osteochondroma has pathognomonic features, specifically continuity of the medullary space with the underlying bone. Three classical appearances have been described. Firstly, an enlarged condyle with anteromedial extension into the lateral pterygoid.[44] Second is the ‘shredded flag’ appearance with a mass arising from the lateral aspect of the condyle. Finally, is a lesion originating from the medial aspect of the condyle, better appreciated on CT imaging.

CT imaging will give a more 3-dimensional appreciation when assessing the lesion and allow better pre-operative planning; this can often be completed as a cone-beam CT with reduced radiation doses.[16] It is recommended that any patient undergoing surgical removal of an osteochondroma of the condyle should have an MRI to assess the articular disc form and location.[17]

Osteoblastoma

Radiographic findings are mixed for these lesions; alternating regions of radiolucency and radiopacity are observed depending on the degree of calcification.[35] Osteoid osteomas are classically described as having a sclerotic border.[43] Larger osteoblastomas lack this border, either representing a different entity or an expansion.[31]

Treatment / Management

Osteosarcoma

Osteosarcoma is primarily managed surgically, with 1.5 to 2 cm margin excision.[39] Following this wide resection, reconstruction may be required through the likes of free tissue transfer or obturators. Obtaining clear margins is the most strongly prognostic factor for osteosarcoma.[32] If the tumor is in a problematic anatomical location, is aggressive, or margins are involved, neoadjuvant or adjuvant chemotherapy may be options.[39] Radiotherapy is not required, and neck dissections are rarely performed. (B2)

Fibrous Dysplasia

Fibrous dysplasia bony expansion stabilizes as bony maturity is achieved; therefore, the timing of any intervention must be closely considered in light of the patient’s age. Patients with a milder degree of deformity will require no surgery as they adapt to the facial expansion. Surgical management consists of debulking and recontouring. While the bony skeleton is still growing, the fibrous dysplasia is in a more active phase, and therefore recurrence is more likely to occur. It is, therefore, preferable to wait until adulthood before surgical intervention is undertaken.[33][40]

Central Giant Cell Granuloma

These lesions can be treated via surgical and non-surgical means. The surgery varies depending on the location, size, and aggressiveness of the lesion and can range from curettage to large-scale resection and reconstruction.[9][11][24] Non-surgical treatment is often considered for smaller, less aggressive lesions; however, some have suggested its use as neoadjuvant therapy for large lesions. Intralesional steroids, daily subcutaneous calcitonin, and interferon-alpha for its antiangiogenic effects have all been used with some success.(B2)

Osteoma

As a benign, slowly growing pathology, the management of osteoma is dependent on the symptoms it produces. When small and not causing any functional or aesthetic distortion, it can be monitored.[45] However, in symptomatic cases, surgical excision is recommended. This is normally carried out as a complete, close-margin excision, most often through an intra-oral approach.[15](B2)

Osteochondroma

Treatment is dependent on the size and location of the osteochondroma. Generally, they required surgical excision, as their location in the joint impinges function. If the entirety of the condyle is involved, a condylectomy is performed and most commonly reconstructed with alloplastic total joint prostheses.[30]  Smaller tumors involving less than half of the condylar head can generally be excised directly.[17] Coronoid osteochondromas are removed through a coronoidectomy. Orthognathic surgery can also be undertaken to correct any associated dentofacial deformity.[16](B2)

Osteoblastoma

The main obstacle to treatment for osteoblastoma is diagnostic certainty. Treatment is case-specific, depending on the aggressiveness of the tumor. Some cases are well managed with local curettage, whereas others undergo wide margin resections.[18] There have been reports of osteoblastoma undergoing radiation-induced malignant transformation to osteosarcoma; therefore, radiotherapy is not recommended.[19] In the case of an aggressive tumor in a young individual, chemotherapy could be considered. In the case of recurrence, careful scrutiny is necessary to distinguish between true recurrence and spontaneous transformation to osteosarcoma.[46](B3)

Differential Diagnosis

Osteosarcoma

• Osteoblastoma – it can be very difficult to distinguish between low-grade osteosarcoma and an aggressive subtype of osteoblastoma. Osteoblastomas are benign and do not metastasize.
• Ossifying fibroma – can be distinguished by absent extracortical bone loss.
• Osteomyelitis – will produce a similar moth-eaten appearance on radiographs with extra-cortical bone loss but has a differing clinical course and is unlikely to cause paraesthesia, a feature of perineural invasion.

Fibrous dysplasia

The primary differential for fibrous dysplasia is other fibro-osseous conditions.

• Ossifying fibroma – histologically indistinct from fibrous dysplasia, this is more commonly in tooth-bearing areas and has well-defined radiolucency.
• Segmental odontomaxillary dysplasia – this causes failure of maxillary pre-molar eruption with gingival hyperplasia.
• Paget’s disease – seen in an older population, more commonly associated with pain and altered bone profile.

Central giant cell granuloma

Giant cell granulomas can be seen in other systemic conditions; it is, therefore, vital to exclude these.

• Brown’s tumor of hyperparathyroidism – histologically indistinguishable but normally present in multiple and with deranged bone profile results.
• Cherubism – this is an autosomal dominant disorder, most commonly caused by a mutation in SH3P2. It causes widespread and multiple osteolytic lesions of, primarily, the posterior mandible. Onset is in childhood, producing a classical, symmetric full-cheek appearance.[27]
• Noonan syndrome
• Neurofibromatosis type I
• Aneurysmal bone cysts 

Osteoma

• Bony exostoses – differentiated by lack of further growth following puberty, most are lobulated and multifocal.
• Osteoid osteoma – pain is a more prominent feature, and faster expansion is present.
• Late-stage, central ossifying fibroma – borders are well defined, with a surrounding sclerotic border presenting as a thin radiolucent line.
• Complex odontoma – demonstrates greater density on radiographic assessment.

Osteochondroma

Generally, due to their pathognomonic radiographic features, osteochondromas can be identified from plain films.

• Malignant lesions, i.e., chondrosarcomas and osteosarcomas - will have aggressive spread, causing surrounding soft tissue damage, leading to symptoms such as paraesthesia.
• Condylar hyperplasia – proportionate growth with regular contours of the condyle.
• Hemimandibular hyperplasia – Anomaly of the entire mandible involving ramus and body.

Osteoblastoma

• Osteoid osteoma – may represent an early phase of the disease or be a separate entity. Clinically distinguished by smaller size (<2cm), pain worse at night, and good response to salicylates and non-steroidal anti-inflammatories.
• Low-grade osteosarcoma – distinction can be difficult with similar histology. Osteosarcoma can cause lung metastases and is more likely to cause surrounding neural dysfunction.
• Cementoblastoma – round radiopacity, normally at apical half of single-rooted tooth causing pain, odontogenic in origin.
• Ossifying fibroma – mixed radiolucency, spherical in shape, pain is not a prominent feature.

Prognosis

Osteosarcoma

Osteosarcoma is an aggressive, metastatic malignancy. The types seen in the jaws are less aggressive and have a better prognosis than those in the axial skeleton. The risk of lung metastasis is 20 to 25%.[47][48] At five years, the overall survival rate for a non-metastatic disease with clear margins is 77%. Obtaining a clear margin is the weightiest prognostic factor; 3-year survival drops from 100% to 38% with incomplete resection.[32][49] Other prognostic factors include age >60 years, high histological grade, tumor location, and, in some studies, the use of adjunct chemotherapy. Local recurrence is more common than metastasis.

Fibrous Dysplasia

Malignant transformation, although very rare, can occur (1%).[33] It is more commonly seen in those who have undergone radiotherapy. Transformation is to osteosarcoma. However, fibrosarcoma and chondrosarcoma have also been reported.[7]

Central Giant Cell Granuloma

Central giant cell granuloma can have aggressive, locally destructive behavior or may be indolent and respond to non-surgical therapies. The recurrence rate is higher in these aggressive forms, particularly if incompletely removed. Recurrence normally occurs within the first 12 to 18 months.[50] In more aggressive lesions, a high recurrence rate is seen, reported between 40 to 70%.[26]

Osteoma

Osteomas have a good overall prognosis, recurrence following surgical excision is exceedingly rare, and there are no reported cases of malignant transformation.[13][15]

Osteochondroma

Excision is usually curative. The recurrence rate is low and elsewhere in the body, reported at 1 to 2%. There are only two reports within the literature on the malignant transformation of craniofacial osteochondromas.[30][51]

Osteoblastoma

Osteoblastoma has a high recurrence rate, reported at up to 20%.[19] They can undergo a spontaneous malignant transformation or actually represent low-grade osteosarcoma. Therefore, it is important to closely follow up with these patients with clinical and radiographic examination.

Complications

Osteosarcoma

Complications are inherent to the malignant nature of the condition. Significant morbidity is associated with wider resection of the jaws and needs for subsequent reconstruction.

Fibrous Dysplasia

Fibrous dysplasia can cause marked facial asymmetry in children and adolescents, and it can therefore cause a large degree of distress to patients and their families. Complications are from specific surgical intervention and the risk of regrowth if the patient is in the active phase. 

Central Giant Cell Granuloma

Complications can occur due to the destructive nature of central giant cell lesions, particularly loss of dentition or tooth buds.  When cortical bone erosion occurs around nerves, specifically the inferior alveolar nerve, impingement can occur. As it does not exhibit perineural invasion but only impingement, once repositioned, the inferior alveolar nerve function is restored.[9][10]

Osteoma

Complications from osteomas can be either related to their functional impact or the surgery performed to remove them and are therefore related to their location and surrounding anatomical structures.

Osteochondroma

Complications of osteochondromas occur due to their impingement of temporomandibular joint function and surgical intervention. These are not normally specific to osteochondromas but to temporomandibular surgical intervention generally.

Osteoblastoma

When small and managed with local curettage, complications may be minimal. However, when representing an aggressive subtype, high morbidity and small numbers of reported mortalities may be observed.[20]