Osteosarcoma is an aggressive malignant mesenchymal tumor that produces osteoid tissue or immature bone in malignant cells. Although it is the predominant primary malignant tumor of bone in children and adolescents, its prevalence in the jawbones is relatively low, representing less than 10 percent of all cases of osteosarcoma [1]. Osteosarcoma of the jaw (OSJ) has different biological behavior than long-bone osteosarcomas, growing more slowly, having reduced potential to metastasise, and prognosis. Nevertheless, regardless of these distinctions, its diagnosis and treatment still remain major challenges to clinicians [2]. Early and proper diagnosis is one of the biggest challenges in the treatment of OSJ. The clinical picture is usually not specific and can appear as swelling, pain, tooth looseness or paraesthesia [3]. These symptoms are often confused with odontogenic infections or benign lesions of the jaw with a consequent delay in diagnosis. OSJ radiographically may resemble other intraosseous lesions like osteomyelitis, fibrous dysplasia or chondrosarcoma. The typical appearance of the sunburst is not always seen in the jaw which makes it even harder to diagnose [4]. Even the histopathological examination is unacceptable, but even in this case, it can be difficult because of the histological heterogeneity of osteosarcoma and overlapping with other spindle cell tumors. Consequently, oral surgeon, radiologist, and pathologist input are essential to identify them on time [5]. OSJ also has a complicated management. Wide local resection is regarded as the gold standard because complete resection with tumor-free margins is the single most significant factor predicting survival and local control. The maxillofacial area is however not easy to achieve clear margins because it is close to vital organs like the orbit, cranial base and neurovascular bundles [6]. This structural constraint usually results in poor resections and contributes to the high rates of local recurrence. Chemotherapy and radiotherapy were extensively studied as adjuvant therapies, yet the effectiveness of adjuvant therapy in the context of OSJ remains controversial. In contrast to the long-bone osteosarcomas, OSJ does not seem to respond to the standard chemotherapy lines well enough, and the value of radiotherapy is still debatable due to the risks of radioresistance and developing secondary sarcomas [7]. In OSJ, the prognosis depends on a number of factors, such as tumor size, location, histological subtype, sufficiency of surgical margins, and the presence of metastasis. Although the survival rate of OSJ is usually higher than of appendicular osteosarcoma, recurrence is more common and is the primary cause of treatment failure. Additionally, aggressive maxillofacial resections with ensuing functional and aesthetic impairments are further psychosocial burdens on patients, especially on young adults in the socially productive phase of life [8]. Reconstructive issues also exacerbate post-operative rehabilitation and demand complicated microsurgery and follow-up. Recent progress in the molecular biology and immunohistochemistry has provided a new Mediterranean of insight into the pathogenesis of OSJ. TP53, RB1 and MDM2 alterations, including mutations that cause tumorigenesis, have been identified as genetic alterations that can be exploited to manufacture targeted therapies in the future [9]. In the same manner, studies of early detection biomarkers and predictors of response to chemotherapeutic agents could ultimately enhance personalized therapeutic approaches. But the existing evidence is insufficient and disjointed, and mostly it is resting on small retrospective studies, and clinicians find themselves in a perennial dilemma on how best to diagnose and treat it [10]. In the light of these uncertainties, osteosarcoma of the jaw remains a vexation to maxillofacial surgeons, oncologists and pathologists. Even after decades of research, the questions about the best diagnostic regimen, the best adjuvant therapies, and the long-term functional outcomes are unanswered. The purpose of the review is to critically review the literature available on osteosarcoma of the jaw, outline the diagnostic challenges, treatment considerations, and future outlooks regarding what can be done to help patients. Review Epidemiology and Clinical Characteristics: The most common primary bone malignancy is osteosarcoma, but its occurrence in the jaw is uncommon with only 5-10 percent occurrence. In contrast to typical osteosarcoma of the long bones, which reaches its maximum between adolescence and adulthood, Osteosarcoma of the jaw (OSJ) is a disease that is found in the late third to fourth decade of life. OSJ clinically appears with swelling, pain, tooth mobility and sometimes paraesthesia of the inferior alveolar nerve. Often these signs resemble odontogenic or inflammatory states, which causes delayed suspicion. OSJ is relatively less prone to distant metastasis compared with long-bone osteosarcomas, but exhibits a high likelihood of local recurrence; thus, local control is of utmost importance [11]. Diagnostic Challenges Clinical and Radiographic Dilemmas: The presentation of OSJ in the nonspecific form is often confounded with benign lesions of the jaw and tumors of odontogenic nature. Radiographically, osteosarcoma can appear in form of mixed radiolucent-radiopaque lesions with ill-defined margins. The typical classical periosteal response of the sunburst or Codman triangle is most often not observed in the jaws, which complicates the interpretation of radiographs even more. Cone-beam computed tomography (CBCT) and MRI are useful in the evaluation of cortical destruction and soft tissue invasion [12]. Histopathological Complexity: Histopathology remains the gold standard of diagnosis but has been linked with many pitfalls including histopathological heterogeneity. They include osteoblastic, chondroblastic and fibroblastic subtypes which may overlap with other spindle cell sarcomas. Immunohistochemistry could help in diagnosis, and SATB2, osteocalcin, and osteonectin are markers of osteoblastic differentiation. No pathogenomic marker, however, exists [13]. Role of Molecular and Genetic Studies: Recent discoveries have established genetic changes such as TP53 and RB1 mutations, MDM2 amplification, as well as dys-regulation of Wnt/b-catenin pathway. Although such findings contribute to a better understanding of tumor biology, their use in daily diagnosis is insigni

Treatment Modalities and Challenges Surgery : Treatment is based on wide local resection with tumor-free margins. Nevertheless, radical resections are challenging due to the anatomy of the maxillofacial area with its functional and aesthetic significance. Positivity of the margin is closely related to recurrence and poor prognosis. Long-term rehabilitation is problematic, although reconstructive surgery with free flaps (fibula, iliac crest, scapula) is frequently necessary. Chemotherapy: Chemotherapy plays an important role in the survival of osteosarcoma of the long bone. But chemotherapy is controversial in OSJ. A number of studies indicate that OSJ is less sensitive to chemotherapy, and that it has minimal effect on survival. Neo-adjuvant chemotherapy has been tried to downstage tumours with variable success. Radiotherapy OSJ is traditionally regarded as radioresistant and is not very responsive to radiotherapy. Nonetheless, it can be employed as an adjunct to the presence of positive surgical margins, unresectable tumors or palliation. The development of new radiotherapy systems like intensity-modulated radiotherapy (IMRT) and proton therapy can offer a better local control at a lower toxicity level [15,16] . Prognostic Factors Prognosis in OSJ is generally better than in long-bone osteosarcoma, with 5-year survival rates ranging from 40–70%. Key prognostic determinants include: • Surgical margin status – the single most important predictor. • Tumor size and location – maxillary tumors fare worse due to complex anatomy. • Histological subtype – chondroblastic subtype is associated with poorer prognosis. • Presence of metastasis – rare but portends poor outcomes. Recurrence remains the most significant clinical issue, with rates reported as high as 40–60% [17]. Emerging Directions Molecular Targeted Therapies Research into targeted therapy, such as inhibitors of VEGF, mTOR, and immune checkpoint molecules, is ongoing. Although still experimental, these may open avenues for improved systemic control in the future. Biomarkers for Early Detection Circulating tumor DNA, microRNAs, and immunohistochemical markers are being studied as potential tools for early detection and prognostication. Personalized Medicine Advances in genomic profiling may enable stratification of patients for individualized therapy, improving survival and minimizing overtreatment [18].

Table 1: Summary of Osteosarcoma of the Jaw – Key Aspects, Challenges, and Emerging Directions Section Key Points Epidemiology & Clinical Characteristics - Osteosarcoma most common primary bone malignancy; OSJ only 5–10%. - Peak: late 3rd–4th decade (vs adolescence in long bones). - Clinical: swelling, pain, tooth mobility, paraesthesia. - Mimics odontogenic/inflammatory lesions → delayed diagnosis. - Less prone to metastasis, but high local recurrence. Diagnostic Challenges Clinical/Radiographic: - Overlaps with benign lesions. - Radiographs: mixed radiolucent–radiopaque, ill-defined margins. - 'Sunburst' / Codman’s triangle rare. - CBCT/MRI: assess cortical destruction & soft tissue. Histopathology: - Gold standard but heterogeneous (osteoblastic, chondroblastic, fibroblastic). - Overlaps with spindle cell sarcomas. - IHC: SATB2, osteocalcin, osteonectin (not pathognomonic). Molecular/Genetic: - TP53, RB1 mutations, MDM2 amplification, Wnt/β-catenin dysregulation. - Clinical use limited. Treatment Modalities & Challenges Surgery: - Wide resection standard, margin positivity → recurrence. - Reconstruction with free flaps (fibula, iliac crest, scapula). Chemotherapy: - Standard in long-bone OS, controversial in OSJ (less chemosensitive). - Neoadjuvant use: variable benefit. Radiotherapy: - Traditionally radioresistant. - Adjunct for positive margins, unresectable tumors, palliation. - IMRT, proton therapy promising. Prognostic Factors - Prognosis better than long-bone OS. - 5-year survival: 40–70%. - Key determinants: • Margin status (most important). • Tumor size/location (maxillary worse). • Histological subtype (chondroblastic worse). • Metastasis (rare, poor outcome). - Recurrence 40–60%.

The diagnosis of OSJ remains one of the most pressing challenges due to its overlapping clinical, radiographic, and histopathological features with other maxillofacial lesions. Clinical Ambiguity The patients usually have swelling, pain, tooth mobility, or paraesthesia. These symptoms closely resemble odontogenic infections, periodontal disease or benign fibro-osseous lesions. More often than not, patients go through extractions, root canal or incision and drainage prior to any suspicion of a malignancy. This leads to a major delay in diagnosis which directly influences the results of treatment [19]. Radiographic Pitfalls OSJ radiographic appearances are infamously unspecific. These classical features are not likely to be seen in the jaws as in long-bone osteosarcoma the sunburst appearance or Codmans triangle is relatively frequent. Rather, OSJ tends to present in the form of poorly defined radiolucent or mixed radiolucent-radiopaque lesions, which resemble fibrous dysplasia, ossifying fibroma, or chronic osteomyelitis. Even sophisticated imaging like CBCT and MRI will be useful in identifying cortical destruction and soft tissue infiltration, but it will never accurately differentiate OSJ and other intraosseous malignancies [20]. Histopathological Overlaps Even in histopathology which is the gold standard, diagnostic dilemmas in this category still occur. OSJ is characterized by a high degree of heterogeneity comprising osteoblastic, chondroblastic, and fibroblastic variants that are morphologically indistinguishable to either chondrosarcoma, fibrosarcoma, or malignant fibrous histiocytoma. The small biopsies are not able to identify diagnostic osteoid formation resulting in misdiagnosis. SATB2, osteocalcin and osteonectin can be used as immunohistochemical markers to confirm, but none is absolutely specific. Therefore, several biopsies and the services of a professional pathologist may be needed [21]. Limited Role of Molecular Diagnostics Even though molecular markers, including TP53 and RB1 mutation, and MDM2 amplification, are becoming more and more commonly known, their application in clinical practice is limited. Genetic testing is not widely done in most centers, nor are the results very specific. As a result, the usage of molecular studies is restricted to the research context only, and clinicians have to cope with traditional yet incomplete diagnostic methods [22]. Treatment Dilemmas in Osteosarcoma of the Jaw Even after diagnosis, management of OSJ presents multiple challenges due to the unique anatomical and biological features of jaw tumors. Surgical Challenges The basis of treatment is wide local resection with tumor-free margins. Nevertheless, oncologically safe margins of the maxillofacial skeleton are not easily realized due to the closeness to vital organs like the orbit, cranial base, and neurovascular bundles. This leaves surgeons with the dilemma between radical resection that leaves the patient with profound functional and cosmetic deficits, or more conservative surgery that are more likely to recur. Moreover, free flaps reconstruction surgery is a challenging, expensive and not always possible technique in a resource constrained environment [23]. Controversies in Chemotherapy Although chemotherapy has significantly increased the survival of long-bone osteosarcoma, its use in OSJ is somewhat controversial. Some studies indicate that OSJ has reduced chemosensitivity, and minimal effect on recurrence and survival. The chemotherapy used routinely in long bone cases to shrink tumors and determine chemosensitivity, neo-adjuvant chemotherapy does not always benefit jaw osteosarcomas. The dilemma is whether patients ought to receive potentially toxic courses of chemotherapeutic treatment that may have unconclusive survival benefit [24]. Radiotherapy: To Use or Not to Use? Osteosarcoma has traditionally been regarded as radioresistant with little response to radiotherapy. In OSJ, however, positive margins, unresectable tumors or palliation are sometimes treated with radiotherapy. The problem is that radiotherapy poses risks of osteoradionecrosis, secondary sarcomas, and poor healing of the jaw, and makes surgical reconstruction more difficult. There is some hope that emerging modalities such as proton beam therapy and intensity-modulated radiotherapy (IMRT) will be able to provide better local control with fewer side effects, although they are not widely available yet [25]. Prognosis and Recurrence Despite having high survival rates compared to long-bone osteosarcoma, OSJ is associated with high rates of recurrence following the inability to achieve wide margins. Every recurrence requires a more aggressive resection, resulting in a higher degree of morbidity and lower quality of life. The quandary is striking a balance between radical oncologic excision and preservation of function and appearance in an area of speech, mastication, and appearance [26]. Future Treatments Antibody–drug conjugates (ADCs) represent a promising therapeutic avenue for osteosarcoma of the jaw, as they combine tumor-specific monoclonal antibodies with potent cytotoxic payloads, enabling selective targeting of malignant cells while sparing normal tissues. Potential molecular targets currently under investigation in osteosarcoma include HER2, GD2, and IGF-1R, all of which are variably expressed in sarcoma cells. By exploiting these surface antigens, ADCs may improve local tumor control, reduce systemic toxicity, and overcome the limited chemosensitivity that characterizes conventional therapies in jaw osteosarcoma [27]. Differential Diagnosis The differential diagnosis of osteosarcoma of the jaw (OSJ) is broad, as its clinical and radiographic features often overlap with both benign and malignant lesions of the jaws. Ossifying fibroma is one of the key considerations, as it presents as a well-circumscribed radiolucent to mixed lesion, but unlike OSJ, it shows well-defined margins and concentric bony expansion. Fibrous dysplasia must also be distinguished, particularly because of its characteristic “ground-glass” radiopacity that blends with adjacent bone, lacking the destructive borders and malignant osteoid formation typical of OSJ. Another important differential is chondrosarcoma, a malignant cartilage-forming tumor that can mimic the mixed radiodensity of OSJ radiographically, yet histologically shows lobules of malignant cartilage without osteoid production [28]. Ewing’s sarcoma or primitive neuroectodermal tumor (PNET) should also be considered, especially in younger patients presenting with aggressive jaw lesions. These tumors are composed of small round cells and do not produce osteoid, with diagnosis confirmed by immunohistochemical markers such as CD99. Malignant fibrous histiocytoma (now categorized as undifferentiated pleomorphic sarcoma) is another spindle-cell malignancy that resembles the fibroblastic subtype of OSJ, but lacks malignant osteoid matrix, making histological distinction essential. Chronic osteomyelitis can mimic OSJ radiographically with its “moth-eaten” destructive pattern and periosteal reaction; however, the presence of infection signs and absence of atypical osteoid are distinguishing features. Finally, metastatic lesions to the jaw, though rare, should be considered, especially in patients with a known history of primary malignancy in the breast, prostate, or kidney. These lesions may resemble OSJ but are differentiated by clinical history and lack of osteoid formation [29].

In essence, the diagnostic dilemma in OSJ stems from nonspecific clinical, radiographic, and histopathological features that delay accurate recognition, while the treatment dilemma arises from anatomical constraints, limited efficacy of adjuvant therapies, and the high recurrence rate. These dual challenges keep OSJ in a persistent state of uncertainty, underscoring the need for improved diagnostic markers, better surgical strategies, and evidence-based use of systemic therapies.

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