*5.2.3.1 Central sarcomas*

The main type of central osteosarcoma is the conventional osteosarcoma. Conventional osteosarcoma arising in the head and neck region has the same histologic appearance seen in other locations, being composed of malignant neoplastic cells and lace-like deposition of bone.

Depending upon the predominant-type extracellular matrix present (osteoid, cartilage, or collagen fibers produced by the tumor), conventional OSs are classified into osteoblastic, chondroblastic, and fibroblastic subtypes [13]. All of these subtypes of osteosarcomas can occur in the jaw bones [1].


Traditionally, it has been reported that osteoblastic and chondroblastic subtypes are the most common subtypes. Osteoblastic HNOS have been reported to account for up to 75% of the cases, leaving fibroblastic subtype as the least frequent representing 3–15% of the cases [8, 9, 15].

### *5.2.3.2 Peripheral sarcomas*

Peripheral osteosarcomas are represented by parosteal, periosteal, and high-grade surface.

Osteosarcomas occasionally affect the jaw. The most frequent is parosteal (or juxtacortical) osteosarcoma, which represents less than 5% of all osteosarcomas. It is well differentiated and characterized by spindle cell stroma with minimal atypia and rare mitotic figures separating irregular trabeculae of woven bone, arranged in a parallel manner. Even in histopathology, peripheral osteosarcoma could have osteoblastic, fibroblastic, or chondroblastic differentiation.

Approximately 10–25% of parosteal osteosarcomas dedifferentiate into high-grade osteosarcoma with a corresponding worsening of prognosis [13].

**Figure 6** shows the histology of the patient presented in **Figure 1**.

### *5.2.4 Histological grading*

Histologic grade is a key part of the microscopic description of a HNOS, as it has been shown to be an independent prognostic factor. Its importance is such that nowadays, it constitutes part of the information required for staging. However, there are still substantial differences in the various expert groups on how to measure and report it.

Some authors report tumors as classified into high and low grade, as others use three categories: high, intermediate, and low. The large series to date report the histologic grade in four levels, with low grade being levels 1 and 2 and high grade, levels 3 and 4 [8, 9]. In addition, apart from different classification groups in terms of grade, there is high interobserver variability, thus making the grading reproducibility poor.

As far as consensus is concerned, cellularity and mitosis are the most important criteria used for histological grading. In general, the more cellular a tumor is, the higher is the grade. With increased cellularity, tumor loses the trabecular bone architecture and more nuclear atypia appears. Irregularity of the nuclear contour, enlargement, and hyperchromasia of the nuclei are correlated with grade.

Some authors state that the majority of HNOS are high grade [6]. Ha et al. reported up to 76.9% high-grade HNOS in a series of 27 patients [21]. Similarly grade was reported on 60 of 119 patients treated at MD Anderson Cancer Center, informing low grade on 22%, intermediate on 15%, and high grade on 63%. However, on larger series, high-grade tumors represent about 30–40% of the cases. On the.

series by Lee et al., analyzing the SEER database on 2011, with 541 HNOS patients, 40.9% of all tumors were diagnosed to be high grade at presentation, 19.6% low grade, and 39.5% were unknown [9]. In Smith et al. analysis of the NCDB database on 1996, with 496 cases, tumor grade was reported for 47.4% of the patients, a proportion that increased from 39.6% in the first years (1985–1991) to 55.9% in the later years (1992–1996), probably as the importance of histologic grading on treatment planning and prognosis became evident. In this study, of the patients with a reported grade, 38.3% had well-differentiated or moderately well-differentiated tumors, 35.7% had poorly differentiated tumors, and 26.0% had undifferentiated tumors. Interestingly, authors also report that the percentage of high-grade tumors increased as tumor size increased. Also, although mandibular tumors were distributed evenly,

with 46.9% low-grade tumors (Grade 1–2) and 53.1% high-grade tumors (Grade 3–4), a greater percentage of skull and facial bone tumors were high-grade lesions (67.4% and 70%, respectively) [8].

### *5.2.5 Immunohistochemistry*

Immunohistochemistry (IHC) plays an important role in clarifying the differential diagnoses between low grade sarcomas and fibro-osseous lesions and between chondrosarcoma and chondroblastic OS.

Focal positivity with CD68 suggests fibrohistiocytic nature of the tumors to be one of the variants of OS. Previous studies have analyzed the clinicopathological features and immunohistochemical expression of p53, MDM2, CDK4, PCNA, and Ki67 proteins in head-and-neck OS and found PCNA as one of the most favorable prognostic markers [1].

The immunohistochemistry such as Ki67, MDM2, and CDK4, is useful in diagnostic confirmation for inconclusive cases. Yoshida et al. reported that the combination of MDM2 and CDK4 by immunohistochemical analysis shows 100% sensitivity and 97.5% specificity for the diagnosis of low-grade OS and reliably distinguishes lowgrade osteosarcoma from benign lesions [22].

IHC will show chondrosarcoma to be positive for S100 and vimentin and negative for cytokeratin and epithelial membrane antigen (EMA). Chondroblastic OS will be positive for vimentin, EMA, S100, and rarely cytokeratin.

Fibroblastic OS will be positive for vimentin and S100 negative, thus ruling out the neural tumors [1]. Osteonectin and osteocalcin have been widely used to study OS. Osteocalcin is specific for osteoblasts, whereas the osteonectin is not specific for osteoblasts, but consistently immunostained other cell types such as fibroblasts, pericytes, endothelial cells, chondrocytes, basal layer of the skin epithelium, nerves, and osteoclastic giant cells [23].
