**6.2 Histopathology**

The histopathological type of chordoma (i.e., classic (conventional), chondroid, and dedifferentiated) predicts the prognosis of this tumor. Chondroid chordoma appears in locales where the stroma takes after hyaline cartilage and neoplastic, occasionally physaliphorous cells develop in lacunae. The chondroid variant of chordoma and myxoid chondrosarcoma of cranium base are uncommon tumors and possess the same anatomic location, the clinical presentation sometimes coming about in their amalgamation [19]. But Chordoma and chondrosarcoma have particular histologic and immunohistologic highlights that generally permit for their precise refinement.

Cranium base chordomas emerge from remnants of the primitive notochord at the spheno-occipital synchondrosis, though chondrosarcoma begin from primitive mesenchymal cells or from the embryonic rest of the cartilaginous matrix of the skull. Using immune-histochemical staining they can be differentiated and pathological aspects can be studied. Chondrosarcoma is encompassed of cartilage with pleomorphic chondrocytes [24]. Chordomas comprise uniform cells containing small-oval, eccentric nuclei with prominent chromatin and physaliferous cells which can be identified in histopathology. Chondroid chordoma also possesses a cartilaginous component.

Histologically, chondrosarcomas are considered by a profuse hyaline sort of cartilaginous stroma and the presence of a neoplastic chondrocyte populace. Chondrocytes have an unnoticeable cytoplasm and a small, dark nucleus with fine chromatin. Invasion of the hard trabeculae could be a histological highlight of malignancy. It is strongly identified that chondrosarcomas illustrate recognizable histological grades of separation. Based on mitotic activity, cellularity, atypia, and size of the nucleus, World Health Organization (WHO) presented it in 3 groups namely grade I (well-differentiated), grade II (moderately differentiated), and grade III (poorly differentiated) [25]. Chondrosarcoma grade I and grade II show a better outcome while chondrosarcoma grade III is related with a high recurrence rate as well as metastases. Myxoid chondrosarcoma may be an uncommon mesenchymal soft-tissue malignancy of putative chondrocytic differentiation. Intermittent plain cartilage formation, positivity for S-100 protein, and ultrastructural examination have bolstered this view. In any case, most extraskeletal myxoid chondrosarcomas (EMCs) don't appear chondroid tissue arrangement, and S-100 protein is found in much less common than has been detailed. For the most part, utilizing matrix proteins as markers of mesenchymal cell differentiation explored the biochemical matrix composition and cellular phenotype of the tumor cells in illustrative specimens [26]. Extraskeletal myxoid chondrosarcoma comprises most likely primitive mesenchymal cells with focal, multidirectional differentiation. Chondrocytic differentiation is an abnormal aspect within the range of differentiation patterns displayed by these lesions.

EMC may be a very rare sarcoma subtype that usually ascends in the extremities, in spite of the fact that it can begin from any anatomic location and there are reports of primary EMC of the bone. EMC may occur anywhere exterior to the hard skeleton, synovial layer and the neurocranium and once in a while inside the bones. The histopathologic range of EMC ranges from lesions with densely packed rounded cells to those composed of cords of cells.

Chordomas show up as thick, multi-lobulated, semi-translucent greyish tumors and usually, lesions are 2–5 cm in measure [27]. In typical chordomas, the cells incline to be orchestrated in a set with a pale matrix of mucopolysaccharide with a

*Challenges in Diagnosing Chordoma (Skull Base Tumors) DOI: http://dx.doi.org/10.5772/intechopen.102048*

specific physaliphorous appearance and in development, typical chordomas contain necrosis zone, hemorrhage, and bone trabeculae. Sometimes chondroid chordomas may look like low-grade chondrosarcomas and with the assistance of immunehistochemical observation, these tumors can be distinguished from others [8].

In chondroid chordoma combination of both chordoid and chondroid cells are found. Just in the case of chondromas, some free lying monomorphic cells having blurry cell borders along with faintly stained cell nuclei are usually observed lying within lacunary structures in a background of myxoid material. On histology, chondroid chordomas appear with physaliphorous cells admixed with epithelial cells (characteristic morphology of chordomas) in addition to cartilaginous background. High mitotic activity is also found in the case of chondrosarcomas. Chondromas are uncommon within the pelvis region and ordinarily hypocellular, however, it can be cellular and cytologically atypical. With the assistance of immunohistochemistry, we can differentiate these types of cancer. Prognosis depends on the degree of spread, the treatment choice chosen. Progress in the field of molecular genetics and epigenetics of chordoma and chondrosarcoma, have essentially refined the molecular concept of oncogenesis and hope in coming days it will advance in diagnosis and therapy.

### **6.3 Differential diagnosis**

Chordoma and chondroid chordoma both are immune positive for epithelial markers cytokeratin (CK) and epithelial membrane antigen (EMA), though chondrosarcoma is negative for both [28]. Chordoma show up comparable to fetal notochord on both light and electron microscopy and are immune-histochemically and ultrastructurally similar. Chordoma of the cranium base starts at the spheno-occipital intersection and in soft tissues, they may be encapsulated in contrast to the bony lesion. In microscopy it appears as pseudo-encapsulated by fibrous strands making dense hylanized septa or thin septa creating lobules. Lobules show up as an area of vacuolated physaliferous cells and the sheets of cells contain intracytoplasmic mucin (**Figure 5**). In chondrosarcomas, immunehistochemical stains are negative for CK and EMA and positive for S-100 protein and Vimentin [15].

#### **Figure 5.**

*Photomicrographs from a case of chordoma a) Tumor cells with the lobular arrangement are separated by fibrous septae (microscopic field with 100X in hematoxylin and eosin stain) b) Large bubbly-looking tumor cells with stellate-shaped nucleus and presence of physaliphorous-like cells (microscopic field with 200X in hematoxylin and eosin stain).*

All chondroid and nonchondroid chordomas are positive for cytokeratin and vimentin and in most of the cases they are positive for S-100, EMA, neuron specificenolase (NSE), and carcinoembryonic antigen (CEA). Neoplastic cells within the chondroid zones are stained similarly to those within the tumors. All chondrosarcomas are negative for cytokeratin, EMA, and CEA and are positive for vimentin and S-100. Chowhan et al., 2012 detailed the histological features of chondrosarcomas as a lobular lesional component including large cells with round to mildly pleomorphic vesicular nuclei along with abundant vacuolated cytoplasm lying on a mucomyxoid background (**Figure 6**) [4]. The immune-histochemical positivity of the tumor component for the S100 protein and Vimentin (**Figure 7**) and negative for EMA and CK favored the diagnosis of the myxoid variant of chondrosarcoma over chondroid chordoma [4].

IHC marker Brachyury may is used which is a very precise diagnostic marker for chordomas [29]. Other tumors don't show expression of this protein; hence it can be used as a diagnostic marker for chordomas [30]. It was also found that some differentiated zones of chordomas may show a loss of brachyury immune-reactivity [31]. Synaptophysin and Desmin can be used for staining purposes which is less

#### **Figure 6.**

*Photomicrographs from a case of a myxoid variant of Chondrosarcoma) Tumor cells with the lobular arrangement are separated by fibrous septae (microscopic field with 200X in hematoxylin and eosin stain) b) Large bubbly-looking tumor cells with stellate-shaped nucleus and presence of physaliphorous-like cells (microscopic field with 400X in hematoxylin and eosin stain).*

*Myxoid variant of chondrosarcoma showing cytoplasmic positivity for vimentin (microscopic field with 400X).*

*Challenges in Diagnosing Chordoma (Skull Base Tumors) DOI: http://dx.doi.org/10.5772/intechopen.102048*

pathologically explored. Focal glial fibrillary acid protein (GFAP) immune-reactivity study is another technique that can be explored. Oliveira and his colleagues studied extraskeletal myxoid chondrosarcoma cells with immune reactivity reaction for smooth muscle actin, cytokeratin, polyclonal carcinoembryonic antigen (pCEA), and MIC2 [15]. They have found that all experimental tumor samples lacked the immunoreactivity of the said compounds.

For the histological study of collagen, Masson–Goldner staining may be used [26] as we know collagen is a very important component to study chondroid tumors [26]. Researchers have used to find suitable immune histochemical markers for assisting in the differential diagnosis between chordoma and other tumors with chordoid morphology with biomarkers like GFAP, D2–40, pan-cytokeratin (panCK) etc. Chordoma typically shows positive for panCK and negative for GFAP and D2–40; while chondrosarcoma reveals positive for D2–40, and negative for panCK, and GFAP [32]. To assess the proliferative activity of tumors, Ki-67 immunohistochemistry can be done [33].

### **7. Management**

The primary modality of treatment of chordoma is maximal safe surgical excision of the tumor. This is to ensure maximal cytoreduction & minimizing the morbidity. In most larger-sized tumors complete excision is not technically possible, so some form of adjuvant radiotherapy (preferably with Proton Beam Therapy) is needed [34]. The indications for molecular targeted therapy in chordoma patients are to a great extent based on a number of imminent clinical trials, retrospective studies, and case reports [35]. In any case, the suitability and safety of molecularly targeted therapy regimens in chordoma patients and the fundamental molecular mechanisms, need more efficient research and clinical investigation. Subsequently, novel therapeutic strategies are required to drag out patients' survival and make strides in the quality of lifespan. Pathologically, chordoma emerges from remaining notochord cells inside the vertebral frame, as confirmed on the premise of molecular and immuno-genetic biomarkers [36].

In view of their un-accessible location in the clivus and their cell of origin from the remnants of notochord the Endonasal-Endoscopic surgical Approach (EEA) to these lesions offers an optimal cure [37, 38]. This approach gives the surgeon the most direct access to these tumors in contrast to the open transcranial/facial microscopic approaches which has more morbidity. However, the endoscopic approach requires a higher skill with a steep learning curve for the surgeons. Moreover, as these tumors are locally aggressive, in case of incomplete resection of these tumors, recurrence is the rule [39]. In certain cases, the tumors are large invading the dura mater and very often cause encasement of major intracranial arteries like internal carotid and basilar arteries, etc. In such cases, it is prudent to leave a sleeve of tumor around these critical structures to reduce postoperative morbidity. In this situation other modalities of treatment like proton beam external irradiation offer better locoregional control of the disease [40]. The advantages of proton beam radiotherapy is a very short dose fall-out effect of the proton beams, which helps a better disease control with limited side-effects on the critical structure like the brainstem. However, the proton beam external radiation is very expensive and not available in many centers [41].

#### **7.1 Targeted therapy**

Molecular targeted therapy (**Figure 8**) in chordoma incorporates a) erlotinib, lapatinib, gefitinib, and cetuximab against epidermal growth factor receptor (EGFR) and erbB-2/human epidermal growth factor receptor 2 (HER2/neu); b)

#### **Figure 8.**

*Molecular targeted therapy in Chordoma using some inhibitor of the major signaling pathway that triggers for the progression of Chordoma [42].*

imatinib and dasatinib against platelet-derived growth factor receptors (PDGFR) and stem cell factor receptor [43]; c) sorafenib, pazopanib, and sunitinib that target angiogenic components like vascular endothelial growth factor receptor [44]; and d) temsirolimus and sirolimus that target the phosphoinositide 3- kinase (PI3K)/ AKT/mammalian target of rapamycin (mTOR) pathway [42].

The hairy/enhancer-of-split related with YRPW motif 1 (HEY1; on 8q21.13) gene and the nuclear receptor coactivator 2 (NCOA2; on 8q13.3) [HEY1- NCOA2] gene combination has been recognized in mesenchymal chondrosarcoma [45]. Extraskeletal myxoid chondrosarcoma is additionally a slow-growing soft-tissue tumor containing conspicuous myxoid degeneration and described by extended clinical course despite higher rates of local recurrence as well as metastases. It is characterized by t(9;22)(q22;q12), combining Ewing sarcoma breakpoint region 1 (EWSR1). Other translocation accomplices to Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) incorporate TATA-Box Binding Protein Associated Factor 15 (TAF15) and Transcription Factor 12 (TCF12) [46].

Chordomas are rare tumors that are notoriously refractory to chemotherapy and radiotherapy and the problems of handling aggressive and refractory chordoma have motivated the study of the biological foundations of this disease [11]. Molecular targeted therapy is an alternative way for the treatment of advanced chordoma [11]. The choice of molecular targeted inhibitors for patients with advanced or relapsed chordoma ought to be based on gene mutation screening and immunohistochemistry. Monotherapy with molecularly targeted inhibitors is suggested as the first-line of administration, and combination treatment may be the choice for drug-resistant chordoma. The brachyury vaccine may be a promising strategy and have a great prospect.

#### **7.2 Radiotherapy**

Patients with resectable chordomas, usually radiation therapy [RT] (preoperative, postoperative, or intraoperative) are utilized in conjunction with surgery to improve local control and disease-free survival. For treating spinal/sacral and

*Challenges in Diagnosing Chordoma (Skull Base Tumors) DOI: http://dx.doi.org/10.5772/intechopen.102048*

clival/skull base chordomas, various retrospective studies and case series have demonstrated enhanced local control and disease-free survival with combined surgical/ RT treatments [47, 48]. A meta-analysis of 464 individuals with cranial chordoma found a 68 percent recurrence rate and average/median disease-free survival of 23 and 45 months, respectively, in a meta-analysis [49]. In the treatment of patients with low-grade skull-based and cervical spine chondrosarcoma, proton beam RT, alone or in combination with photon beam RT, has been linked to excellent local tumor reduction and long-term survival. Carbon ion RT has also been shown to have a high local control rate in patients with chondrosarcoma of the skull [50], as well as other unresectable chondrosarcomas [51].

In both cranial and extracranial chordomas, specialized methods such as intensitymodulated radiation therapy (IMRT) and stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT) have been linked to good local control rates [52]. Computed tomography (CT) is used to detect bone deterioration and calcifications in skull base chordomas, whereas magnetic resonance imaging (MRI) is used to define the tumor margin from the brain, characterize the position and extension of the tumor into the neighboring soft tissue structure, and visualize blood vessels [53]. When compared to CT, MRI gives a more precise and superior contrast with surrounding soft tissue, making it useful for assessing recurrent or metastatic lesions [54].
