Open access peer-reviewed chapter - ONLINE FIRST

Challenges in Diagnosing Chordoma (Skull Base Tumors)

Written By

Amit Kumar Chowhan and Pavan Kumar G. Kale

Submitted: November 30th, 2021 Reviewed: December 16th, 2021 Published: February 8th, 2022

DOI: 10.5772/intechopen.102048

IntechOpen
Skull Base Surgery Edited by Hamid Borghei-Razavi

From the Edited Volume

Skull Base Surgery [Working Title]

Dr. Hamid Borghei-Razavi, Dr. Mauricio Mandel and Dr. Eric Suero-Molina

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Abstract

Chordoma is a rare bone malignancy that influences the spine and cranium base. Once in a while, it includes bone and when it does, cranial bones are the favored location. Chordomas emerge from embryonic remnants of the primitive notochord and chondrosarcomas from primitive mesenchymal cells, otherwise from the embryonic rest of the cranial cartilaginous matrix. Chondrosarcomas constitute a heterogeneous group of essential bone malignancy characterized by hyaline cartilaginous neoplastic tissue. Both are characterized by invasion and pulverization of the neighboring bone and delicate tissue with higher locoregional reappearance frequency. Chordoma and chondrosarcoma, especially myxoid variation of chondrosarcoma of the cranium base, are as often as possible amalgamated because of similar anatomic location, clinical presentation, and radiologic sightings, and mixed up histopathological highlights. Chordoma and chondrosarcoma vary with respect to their origin, management strategy, and contrast particularly with respect to outcome. Ultimately, developing indication supports aberrant growth factor signaling as possible pathogenic mechanisms in chordoma. Here, we have shown such a location-based symptomatic predicament, understood effectively with ancillary immunohistochemistry. In this review, we summarize the most recent research findings and focus primarily on the pathophysiology and diagnostic aspects.

Keywords

  • chordoma
  • chondrosarcoma
  • histopathology
  • immunohistochemistry
  • spheno-occiput

1. Introduction

Chordomas are uncommon, locally aggressive malignant bone tumors that develop from the primordial notochord remnants, accounting for 1–4% of all primary malignant bone tumors [1]. Despite the fact that they can form anywhere along the axial skeleton, sacrococcygeal and spheno-occipital locations are most prevalent, followed by cervicothoracic and coccyx [2]. There are also reports of axial destinations and soft tissue involvement. The spheno-occipital synchondrosis of the clivus is the most common source of intracranial chordomas. The origin can be found along the upper clivus (basisphenoid) or along the clivus’ caudal border (basiocciput). Intracranial chordomas can sometimes develop singly from the petrous apex. Chordomas are classified into three categories based on their histological characteristics: classical (conventional), chondroid, and dedifferentiated. Chondroid chordoma is a relatively rare variant that accounts for nearly 14% of all chordomas and is thought to have a better prognosis than classical chordoma [3]. Dedifferentiated chondrosarcoma is a type of cartilaginous tumor that includes two distinct components, namely low-grade chondrogenic components and high-grade noncartilaginous sarcoma. It constitutes 1–2% of all primary bone tumors. Dedifferentiated chondrosarcoma is a rare, highly malignant variant of chondrosarcoma and has a poor prognosis.

Chondrosarcoma is the collective term for a group of heterogeneous, premalignant tumors of bone characterized by the arrangement of hyaline cartilaginous neoplastic tissue. Most conventional chondrosarcomas are low- to intermediate-grade tumors (grade 1 or grade 2). Dedifferentiated chondrosarcoma develops when low-grade conventional chondrosarcoma changes into a high-grade sarcoma, most often showing features of osteosarcoma, fibrosarcoma, or else undifferentiated pleomorphic sarcoma. Mesenchymal Chondrosarcoma (MCS) could be a profoundly malignant tumor showing a Dimorphic histologic design with an exceedingly undifferentiated round cell component admixed with well-differentiated cartilage. The myxoid variant of chondrosarcoma is usually seen in soft tissues, identified as Chordoid sarcoma or parachordoma [4]. Seldom, it includes bone and when it does, cranial bones are the favored location. The prognosis for the majority of patients with chondrosarcoma is relatively favorable and relates to histologic evaluation and satisfactory surgical margins.

In any case, the complex anatomy of the spine and generally expansive tumor volume makes a clean resection ideally challenging, driving to a higher proportion of local relapse as well as distant metastases. Latest disclosures in molecular biology and epigenetics of chordoma and chondrosarcomas have significantly advanced our understanding of the pathobiology of these tumors and offer insight into potential restorative targets.

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2. History

The first macroscopical and microscopical description of chordomas was given by the German pathologist Rudolf Virchow and depicted on autopsy an incidental, little, slimy development on the surface of clivus [5]. Virchow coined the term “chordomata”, and he described its embryonic character and denoted it as ‘ecchondrosisphysaliforaspheno-occipitalis’ which translates to a “cartilaginous physaliphorous” lesion of the cartilaginous junction between basiocciptal and basisphenoid bones [6]. He used the word “physaliphora” to describe the findings during his microscopic observations. Hugo Ribbert, another German pathologist afterwards proposed the term chordoma.

In 1858, German anatomist Johannes Peter Müller hypothesized that chordomata may originate from notochordal tissue. Müller’s hypothesis was based on the point that most vertebrates, counting humans, contain remnants of notochordal tissues but his hypothesis was rejected by Virchow and Luschka (A German anatomist and one of the most prolific anatomical writers of the 19th century) due to a lack of evidence. After a few years later Belgian anatomist Hector Leboucq proposed that notochordal tissue is demolished before human birth [7]. Arnold C. Klebs, a Swiss physician in 1864 first described a patient with spheno-occipital chordomata and afterward in 1889, he stated the first case of cervical vertebrae chordomata. In 1910, physicians Feldmann and Mazzia reported the first official case of a sacrococcygeal Chordoma. In 1919, physician Daland in the USA operated on the first spheno-occipital case. In this year Porter and Daland attempted X-ray treatments on their patient. In 1960, Hungarian neurosurgeons Zoltan and Fenyes noted various initial operation cases to treat cranial chordomas.

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3. Epidemiology

Cranium base chordomas are unusual malignancies with an incidence rate of less than 0.2% among all intracranial neoplasms [8]. Population-based studies also confirmed that the overall frequency of chordomas in a year to be 0.08 per 100,000 persons [8]. All age groups have the chance to be affected with this disease but most of the cases are diagnosed during adulthood and hardly affect children and adolescents. Approximately 0.15% of all intracranial neoplasms are detected as Chondrosarcomas and it is 6% of all cranium base tumors [8].

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4. Pathogenesis

4.1 Origin

In general, it is believed that chordoma cells are initiated from the embryonic notochord remnants [9]. It is also projected that notochordal remnants are derived from the embryonic notochord and reside in the region of an embryo where the embryonic notochord was existing. It is assumed that notochordal remnants stay dormant in maximum cases but might be transformed into malignancies. Yamaguchi and his colleagues have stated a link between persistent notochordal remnants and Chordoma [10]. Currently, cancer stem cell theory has given more details about the embryonic transformations and stem-like cells in Chordoma may show stemness, gene expression, and differentiation [9].

Chordomas may also be an outcome of direct malignant transformation of the notochordal remnant, deprived of a benign notochordal tumor intermediary stage. Otherwise chordoma may be inferred from benign notochordal cell tumor through malignant transformation (Figure 1) making another root of chordomagenesis.

Figure 1.

A schematic presentation of notochord remnant and Chordoma [9].

4.2 Chromosome

Chromosomal changes are found in a few de novochordomas having poorer prognosis and most common genomic alterations are observed in chromosome numbers 1p, 3, 4, 9, 10, 13, and 14 [11]. It was found that chromosomal gain is less common than chromosomal deletion. Bai and his colleagues have identified germline duplication of the TBXT gene that encodes brachyury, a transcription factor that plays an important role in familial Chordoma [12]. A common genetic polymorphism in TBXTis consequently associated with an increased risk for both sporadic and familial chordoma. They have found that PBRM1, B2Mand MAP3K4are the most frequently mutated cancer driver genes in chordoma. Given the role of PBRM1and SETD2in chromatin remodeling, it can be proposed that epigenetic dysregulation may play a vital role in chordoma development. Bai and his group suggested that amplifications of TBXTgene, homozygous deletion of CDKN2Aand mutations in genes like PBRM1, SETD2, ARID1Aetc. are the most common genomic events in sacral Chordoma [12].

4.3 Different pathways

Developing new technologies have widened our understanding of chordoma by implicating innovative pathways to understand the pathogenesis and future therapeutic approach. Alteration in cell-cycle regulation and different signaling pathways have been identified in chordomas. It is also well established that different growth factor signaling is also related to pathogenic mechanisms in chordoma. There are a number of pathways and cyto-molecular factors which are associated with the pathogenesis of chordoma and some are listed in Table 1.

ApproachDescription
Brachyury
  • Expression of this protein is the diagnostic hallmark of chordoma.

  • Encoded by T-Box Transcription Factor T (TBXT) or T gene

  • Germline duplications of the T gene are associated with familial chordomas, whereas somatic tandem T duplications are related with sporadic chordoma.

  • Brachyury is a mediator of epithelial-to-mesenchymal transition by downregulating E-cadherin expression.

  • Ubiquitous brachyury expression in chordoma makes this protein a therapeutic target.

Cyclin-dependent kinase inhibitor 2A (CDKN2A)
  • Upregulation of other T-box genes in malignancy is supposed to repress cell-cycle regulators such as CDKN2A.

  • Tumor suppressor proteins are also encoded by the CDKN2A gene.

  • Mutations of the CDKN2A gene results in uncontrolled cell proliferation through activation of cyclin-dependent kinases 4 and 6 (CDK4/6).

Phosphate and tensin homolog (PTEN)
  • PTEN gene encodes for a tumor suppressor protein.

  • PTEN is a potent cell growth regulator.

  • Numerous chordomas feature loss of PTEN function whereas up-regulation of PTEN has been investigated.

Chromatin Remodeling
  • Pathogenesis of chordoma may involve dysregulation in DNA level resulting in oncogene activation or tumor suppressor silencing.

  • Mutations of Switch/Sucrose non-fermentable (SWI/SNF) gene results in chromatin dysregulation, assisting neoplastic development.

  • SMARCB1 gene is a SWI/SNF component that is supposed to act as tumor suppressor by regulating histone methylation of transcription factor EZH2.

  • Loss of SMARCB1 function acts as a defining marker of poorly differentiated chordomas.

  • Mutations in other SWI/SNF associates like PBRM1, SETD2, ARID1A, etc. have been recognized as probable drivers in chordomas.

Immune Checkpoint: Programmed cell death protein 1/
Programmed Cell Death Ligand 1 (PD-1/PD-L1)
  • Recent immunotherapy trials of chordoma have focused on immune checkpoint regulator, PD-L1, which is responsible for suppressing regulatory T cell apoptosis.

  • PD-L1 expression is also observed on lymphocytes and tumor-infiltrating macrophages at the tumor-stroma interface.

  • Chordomas with negative PDL1 expression is inclined to have further PD-L1 positive tumor-infiltrating lymphocytes (TIL).

  • Prevalence of TIL is associated with metastatic potential.

  • PD-L1 expression in chordomas may be controlled by microRNAs.

T-cell immunoglobulin and mucin-domain 3 (TIM3)/ galectin-9 (Gal9)
  • TIM3 has newly emerged as a target of interest in chordoma immunotherapy.

  • TIM3 endorses survival of the tumor cells by binding to galectin-9 (Gal9) and encouraging T cell exhaustion.

  • TIM3/Gal9 pathway may be an innovative pharmaceutical target for chordoma.

Hedgehog pathway
  • Given the important role of hedgehog signaling in chondrogenesis, therapeutic targeting of this pathway has been investigated.

Platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) signaling Pathways
  • PDGF and EGF signaling have been revealed to increase tumor hyperplasia and tumor survival also.

  • PDGF and EGF bind to a receptor tyrosine kinase resulting in the initiation of regulatory signaling pathways of proliferation and differentiation.

  • Tyrosine kinase inhibitors can selectively block PDGF and EGF receptors phosphorylation and this can be applied for the treatment of chordoma.

PI3K/Akt/mTOR Pathway
  • Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway regulates progression of the cell cycle, cellular proliferation, and survival.

  • Mutations in mTOR and tumor suppressors of PI3K/Akt cascade have been connected with oncogenesis.

  • Skull-based chordoma cells with higher brachyury expression show upregulation of PI3K/AKT cascade genes compared to low-brachyury tumor cells.

  • PI3K/AKT pathway inhibitors decrease brachyury expression.

Insulin-like growth factor 1 (IGF-1) Pathway
  • IGF-1 affects mitogenic activity in bone and its dysregulation may accelerate chordoma development.

  • IGF-1/IGF-1 receptor expression and prognosis in chordomas have been reported.

  • Activation of IGF-1 receptor signaling can thus contribute to the progression of chordoma cells, denoting as a potential biomarker.

Collagen Type II Alpha 1 Chain (COL2A1)
  • COL2A1codes α-chain of type II collagen fibers, a key collagen component of articular cartilage.

  • COL2A1 mutations may generate vital perturbation of matrix deposition and oncogenic signaling of chondrosarcoma.

Extracellular matrix
  • Chordomas produce a plentiful extracellular matrix.

  • Cathepsin K, a cysteine protease may play a role in osteoclast-mediated bone resorption.

  • There is a relation between the expression of cathepsin K and chordoma.

  • Morphogens, signaling molecules that govern embryonic notochord development may play a key role to establish a cellular microenvironment that stimulates chordoma pathogenesis.

MicroRNA (miRNAs)
  • miRNAs are involved in normal chondrogenesis like miR-140 negatively regulates histone deacetylase 4 in non-hypertrophic chondrocytes.

  • Histone deacetylase 4 regulates the chondrocyte hypertrophic phase by inhibiting transcription factor RUNX2 (Runt-related transcription factor 2).

Hypoxia-inducible factor-1α (HIF-1α)
  • Expression of the pro-angiogenic ligand vascular endothelial growth factor (VEGF) is dependent upon HIF-1α.

  • HIF-1α is upregulated under hypoxic environments.

  • During hypoxia, normal and malignant chondrocytes induce HIF-1α expression.

Other molecular targets
  • Phosphatidylinositol-4,5-Bisphosphate 3-Kinase catalytic subunit Alpha (PIK3CA) mutations are key aspects of chordoma pathogenesis and therefore it is a potential target.

  • Receptor tyrosine kinases (RTKs) are the key players in the development and progression of chordoma.

  • Human epidermal growth factor receptor 2 (HER2)/neu is associated with EGF receptor dimer formation.

  • There is a possibility that this heterodimerization upsurges the sensitivity of EGFR-positive chordoma.

Table 1.

Different pathways and cyto-molecular factors associated with the pathogenesis of Chordoma [11, 13, 14].

4.4 Epigenetics

Critically, myxoid chondrosarcoma harbors repetitive genetic rearrangements including the NR4A3 gene, demonstrating an exceptionally useful confirmatory diagnostic indication. Other proteins namely EWSR1 and TAF15 are also involved in this type of cancer. Some researchers also described uncommon combination of transcripts like HSPA8-NR4A3, TFG-NR4A3, and TCF12-NR4A3 which can play a major role in the initiation and development of this malignancy [15]. Currently, no predictive factor is accessible to assist decision making for this metastatic process, and in specific to characterize whether systemic treatment ought to be utilized.

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5. Clinical presentation

Patients with chordomas and chondrosarcomas generally show common and occasionally confusing symptoms, which sometimes delay the diagnosis process until the late stages of the illness [16]. Presentation of the tumors can essentially shift depending on the area of the tumor, expansion, and vicinity of the lesion to basic structures. Visual indications may incorporate obscured vision or loss of vision, ptosis, and visual field defects related to cranial nerve palsies that may be clarified by the area and development pattern of the tumors. It is common for chordoma to invade structures such as petroclival region, parapharyngeal space, cavernous sinus, temporal bone, cerebellopontine point, and infratemporal fossa. Headache, seizures, weakness, vomiting, etc. are the most common symptom in the case of chordoma.

Sacrococcygeal chordoma has different symptomatology based on the location. Most patients usually present with a posterior sacral mass initially and in later stages present with features of sacral pain, lower limb weakness, and/or bladder bowel disturbances.

Other signs and side effects that will show with clival lesions are hypoesthesia, hearing loss, dysphonia, vertigo, dysphagia, dysarthria, dyspnea, and anosmia. Bigger size/volume tumors may likewise compress the brainstem and cerebellum, affecting ataxia, gait disturbances, dysmetria, hemiparesis, or tetraparesis [17]. It is very tough to recognize the nature of the tumor on the basis of the only clinical demonstration. Basic similarities, differences, and treatment difficulties are shown in Table 2.

General featuresChordomas and Chondrosarcomas
Similarity
  • Chordoma and chondrosarcoma of the skull base are rare tumors with overlapping presentations and anatomic locations. Chordomas, mostly occur at the sacrococcygeal region, and at the sphen-occipital region, with nearly all of these occurring at the clivus. Chordoma and chondrosarcoma constitute most primary bone tumors arising within the skull base, both are characterized by invasion and pulverization of the neighboring bone and delicate tissue with higher locoregional reappearance frequency.

  • All age groups have the chance to be affected but most of the cases are diagnosed during adulthood and hardly affect children and adolescents. These diseases affect males more often than females.

  • Chordoma and chondrosarcoma have an alike radiologic and histologic appearance.

  • Display slow growth patterns and cause gradual displacement of neurovascular structures, in sequence leading to the expression of clinical signs and subsequent diagnosis.

  • High tendency for locoregional recurrence with infiltration and obliteration of the surrounding bone and soft tissue.

  • Metastatic potential is considered to be relatively low, distant metastases have been described in patients with advanced disease.

  • Poor prognosis and a lesser survival rate.

Differences
  • Chordomas arise from embryonic remnants of the primitive notochord with a molecular alteration preceding their malignant transformation. Chondrosarcomas originate from primitive mesenchymal cells or from embryonic remnants of the cartilaginous matrix in the cranium.

  • MRI characteristics in de novocases of chordoma, chondroid chordoma, and chondrosarcoma have shown some differences. Most of the chordomas are located in the midline craniovertebral axis whereas in cases of chondrosarcoma the preferred location is paramedian adjacent to synchondrosis [18, 19].

  • Light microscopic examination shows that most chordomas from the base of the skull and spine had classic features. It consists of sheets, nests, and cords of large cohesive cells in a myxoid matrix. Maximum chondrosarcomas are of mixed hyaline and myxoid type and they differ from chordoma by their cytologic and architectural features.

Challenges
  • The multifaceted structure of the cranial base, composed with the close proximity to cranial nerves and vessels, signifies a weighty challenge in the management of these tumors.

  • Aggressive surgery is associated with a considerable risk of high morbidity and mortality and in case of partial resection locoregional recurrence is the rule. Most patients require some kind of adjuvant therapy for disease control.

Table 2.

Similarities, differences, and treatment difficulties of both chordomas and chondrosarcomas.

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6. Diagnosis

Chordoma and chondrosarcoma have a common overview and similar anatomic location, and can be troublesome to recognize some time before the histopathologic and immunohistochemical examination; in any case, tumors have a distinctive origin and distinctive prognosis. Chondroid chordomas, in spite of having a few pathologic characteristics that are comparable to chondrosarcoma, carry on clinically like chordomas. The preoperative separation between chordomas and chondrosarcomas based on the clinical presentation and clinical and instrument-based diagnostics alone is very tough.

Intracranial chordomas usually have a midline cranium base area whereas most chondrosarcomas emerge along the petro-occipital fissure. On the other hand, chondrosarcomas may sometimes have a midline area, making it difficult to differentiate between chondrosarcoma and an intracranial chordoma. In addition, these two tumors have alike signal intensity on T1- and T2-weighted magnetic resonance images. Hence, direct, globular, or arc-like calcifications when present in chondrosarcomas may help to distinguish them from intracranial chordomas [20].

Plasmacytoma and lymphoma sometimes include the cranium base and cause damage to lytic bone. Craniopharyngiomas, other than illustrating a generally characteristic signal intensity, are found more anteriorly in midline than are intracranial chordomas. Other differentials, though uncommon, may include aggressive pituitary adenoma, histiocytosis X, trigeminal neuroma, dermoid and epidermoid cyst.

Neurosurgical methods frequently utilized for the resection of intracranial chordomas and chondrosarcomas are trans-sphenoidal, Cranio-orbito-zygomatic, transbasal, transcondylar, transzygomatic amplified center fossa, and transmaxillary methodologies. Chordomas and chondrosarcomas are not sensitive to chemotherapy and thus the management modality might be a combination of surgical resection with a maximal extraction and adjuvant radiotherapy for both chondrosarcomas and chordomas.

Differential diagnosis includes mainly metastatic carcinoma, chondrosarcoma, and myxopapillary ependymoma. Metastatic carcinoma and chordomas both show positive responses with epithelial markers. It is unusual for metastatic carcinoma to have the lobulated growth pattern of chordoma whereas chondrosarcoma may grow in a lobulated pattern but without fibrous septa. Myxopapillary ependymoma is easy to differentiate from chordoma as they do not stain for epithelial markers [21]. In electron, microscopic view chordoma shows desmosome and mitochondrial rough endoplasmic reticulum complex whereas both are absent in case of chondrosarcoma [22].

6.1 Radiology

Cranium base chordomas are ordinarily found within the midline [18] and appear to start within the bone, penetrating the way of slightest resistance and inevitably creating a soft tissue mass. In spite of the fact that their clinical and imaging presentations are analogous, they infer from distinctive roots. CT and MRI, both are required for accurate characterization of clival chordomas and their association to adjacent anatomy (Figures 2 and 3). Currently, MRI is the most suitable for the radiologic evaluation of intracranial chordomas [23].

Figure 2.

MRI:Expansile lobulated lytic lesion in clivus which is hyperintense on T2 images (a, b) hypointense on T1 (c) image showing heterogeneous enhancement after contrast administration (d) extending into cisterns causing compression over brainstem and displacing basilar artery, lesion is extending into sella (red arrow).

Figure 3.

Figure (a) axial CT brain window and figure (b) axial CT bone window showing subtle lesion on brain window and small lytic lesion on bone window images in a 48-year-old female.MRI images of the same patient 1 year later show the lesion have grown and appear as T2 hyperintense lesion (c), T1 hypointense lesion (d, e) which shows heterogeneous enhancement after contrast administration (f).

Chowhan and his colleagues (2012) studied through MRI of chondrosarcoma and showed a T2 hyperintense lesion involving the clivus, petrous temporal bone, and sphenoid bone [4]. This lesion was hypointense on a T1-weighted image (Figure 4a) and enhanced heterogeneously in the postcontrast (gadolinium) study (Figure 4b).

Figure 4.

Chondrosarcoma: (a) Postcontrast T1-weighted axial image shows heterogeneous enrichment of lesion. (b) Figure showing T1-weighted axial image: Lesion is hypointense on this image.

CT and MRI are essential to decide the tumor localization, as well as the degree of tumor development and the treatment logic, is to maximize tumor resection with reduced morbidity. On susceptibility-weighted imaging the chordoma show multiple areas of blooming which is a nonspecific finding and diffusion-weighted imaging can help to differentiate the conventional vs. dedifferentiated based on cut-off values of apparent diffusion coefficient.

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 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 immune-histochemical 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].

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).

Figure 7.

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

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 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].

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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) 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].

Figure 8.

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

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8. Prognosis

Weber and his colleagues have recognized histology, gross tumor volume, and brain compression as prognostic feature for local control for chondrosarcomas and chordomas as well as overall survival (OS) based on multivariate investigation [55]. Dedifferentiated chordomas usually display a poor prognosis and this subtype contains a 60% 3-year OS compared to an 89.4% 3-year OS for classical chordomas [8]. Bloch and his colleagues have revealed that grade III chondrosarcomas appear with aggressive behavior and are related with the most reduced survival rates [56]. They calculated a 5-year mortality rate was 11.5% in a systematic review of 560 patients with intracranial chondrosarcomas and median survival time of 2 years. The conventional and chondroid variants of chordoma have a favorable long-term prognosis, with a 3-year survival rate of 90% [57]. The dedifferentiated subtype shows aggressive behavior and the 3-year overall survival rate is around 60% [58].

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9. Future aspects

Chordoma may be a malignant tumor with a few confusing highlights, such as its origin, and its neighborhood invasiveness, and moderate aggressive character. To conclude, in spite of the fact that the myxoid variation of chondrosarcoma and chondroid chordoma are comparative in a few viewpoints, they vary in their origin. Cranium base myxoid chondrosarcoma carries an extraordinarily more favorable result with negligible recurrence though chordomas counting its chondroid variant illustrates an aggressive clinical course with consistently destitute outcome after disease recurrence. Radiotherapy is usually suggested after surgery in chordoma, while resection of the tumor suffices in the myxoid variant of chondrosarcoma. Immunohistochemistry is the most common application of immunostaining and it is also widely used to differentiate chondrosarcoma and chordoma and understand the scattering and localization of biomarkers and differentially expressed proteins in different cellular parts of chondrosarcoma and chordoma.

In spite of the advance in current surgical strategies and some encouraging results with the use of targeted therapy, control of the disease and long-term patient prognosis are still not satisfactory. However, understanding of the molecular basis of chordoma pathophysiology hopefully will give us a better understanding to improve the prognosis of this rare malignancy. Currently, surgical resection is the favored treatment for chordoma, whereas recent advances are focused on curative treatment and advanced radiotherapy may play for the treatment of chordoma, and surgery will be done only for the most advanced cases of chordoma.

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Acknowledgments

The author acknowledges the contribution of Dr. Rabi Narayan Sahu, Professor, Neurosurgery, AIIMS, Bhubaneswar for his inputs regarding management protocol, Dr. Rakesh Kumar Gupta, Assistant Professor, Pathology & Laboratory Medicine, AIIMS, Raipur for the contribution of histopathology photomicrograph and Dr. Suman Kumar Ray, PhD (Molecular Biology) for help in writing the manuscript.

Conflict of interest

The authors declare no conflict of interest.

Abbreviations

CK

Cytokeratin

CT

Computed tomography

EGF

Epidermal growth factor

PD-1

Programmed cell death protein 1

PI3K

Phosphoinositide 3-kinase

SWI/SNF

Switch/Sucrose non-fermentable gene

CDK4/6

Cyclin-dependent kinases 4 and 6

CDKN2A

Cyclin-dependent kinase inhibitor 2A

CEA

Carcinoembryonic antigen

COL2A1

Collagen Type II Alpha 1 Chain

EGFR

Epidermal growth factor receptor

EMA

Epithelial membrane antigen

EMC

Extraskeletal myxoid chondrosarcomas

EWSR1

Ewing sarcoma breakpoint region 1

Gal9

Galectin-9

GFAP

Glial fibrillary acid protein

HER2

Human epidermal growth factor receptor 2

HEY1

Hairy/enhancer-of-split related with YRPW motif 1

HIF-1α

Hypoxia-inducible factor-1α

IGF-1

Insulin-like growth factor 1

IHC

Immunohistochemistry

IMRT

Intensity-modulated radiation therapy

MCS

Mesenchymal chondrosarcoma

miRNAs

MicroRNA

MRI

Magnetic resonance imaging

mTOR

Mammalian target of rapamycin

NCOA2

Nuclear receptor coactivator 2

NR4A3

Nuclear Receptor Subfamily 4 Group A Member 3

NSE

Neuron specific enolase

OS

Overall survival

panCK

Pan-cytokeratin

pCEA

Polyclonal carcinoembryonic antigen

PDGF

Platelet-derived growth factor

PDGFR

Platelet-derived growth factor receptors

PD-L1

Programmed cell death ligand 1

PIK3CA

Phosphatidylinositol-4,5-Bisphosphate 3-Kinase catalytic subunit Alpha

PTEN

Phosphate and tensin homolog

RTK

Receptor tyrosine kinases

RUNX2

Runt-related transcription factor 2

SRS

Stereotactic radiosurgery

SRT

Stereotactic radiotherapy

TAF15

TATA Box Binding Protein Associated Factor 15

TBXT

T-box transcription factor T

TIL

Tumor-infiltrating lymphocytes

TIM3

T-cell immunoglobulin and mucin-domain 3

VEGF

Vascular endothelial growth factor

WHO

World Health Organization

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Written By

Amit Kumar Chowhan and Pavan Kumar G. Kale

Submitted: November 30th, 2021 Reviewed: December 16th, 2021 Published: February 8th, 2022