Chordoma Workup

Evaluation of chordoma revolves around imaging and biopsy. ^[1] No laboratory studies are required for evaluation of chordoma, except as needed for routine preoperative evaluation for patients scheduled to undergo surgical resection. Plain radiographs may be useful to demonstrate the extent of bone involvement. Plain film radiographs may show an ill-defined endosteal margin or a bulky mass in the soft tissue. These lesions may be lytic. In general, and especially in clival chordoma, erosion of bone, particularly the tip of the clivus, and a sclerotic bone reaction are seen radiographically. The mass appears as a destructive, well-demarcated lesion. Discovery of these features can better clarify the diagnosis of chordoma in the differential of bony lesions.

Computed tomography (CT) imaging is better for demonstrating the destructive lytic chordoma. Occasionally, the chordoma will have sclerosis at the margin. Chordomas are hypodense compared to bones on CT and may demonstrate irregular dystrophic calcification. Chordomas show moderate to significant enhancement on contrast CT imaging. ^[1]

Magnetic resonance imaging (MRI) best delineates the extent of a chordoma. Chordomas have lower signal intensity on T1-weighted imaging and may show foci of hyperintensity, which represent intratumoral hemorrhage. T1-weighted imaging with gadolinium contrast demonstrates heterogeneous contrast enhancement of the tumor with a honeycomb appearance. On T2-weighted imaging, chordomas tend to be hyperintense. Gradient-echo MRI can confirm intratumoral hemorrhage. ^[1]

Bone scans are sometimes obtained during the workup, and chordomas are known to have normal to decreased uptake. ^[1]

On MRI, the appearance of a chordoma is similar to its appearance on CT scan, with better resolution of the soft tissue component, resulting in better anatomic definition, as depicted in the image below. Chordomas are hyperintense on T2 images and hypointense on T1 images.

 

Imaging of the clivus usually reveals features adequate for differentiating chordomas from other site-specific lesions. In the sacrum, radiographic features are more similar to those of other common bone tumors, and although they may be suggestive of a chordoma, they are not diagnostic.

Biopsies of chordomas are useful only when other bone lesions remain in the differential diagnosis after imaging studies are performed. In this instance, tissue diagnosis by biopsy can enable optimal planning for surgical resection of the tumor. Fine-needle aspiration (FNA), the preferred method for establishing the preoperative morphologic diagnosis of chordoma, has been reported to lower local recurrence rates when compared with open biopsy. ^[18] Diagnostic criteria for chordoma in FNA include the presence of physaliphorous cells with round nuclei, bland chromatin, and distinct cytoplasmic borders in a background of abundant myxoid ground substance.

Many times, a needle or open biopsy is performed to confirm the diagnosis of chordoma. Care must be taken when the biopsy is planned and performed, as the chordoma can seed along the biopsy tract. Thus the biopsy tract should be included in the future chordoma resection to decrease the risk of local recurrence. ^[1]

Chordomas are divided into conventional, poorly differentiated, dedifferentiated, and chondroid types.

Chordomas show notochordal differentiation and are characterized by nuclear expression of brachyury (TBXT). Chordomas are localized in the axial skeleton, where they occur from the clivus to the sacrococcygeal region. They are slow-growing, locally destructive tumors that often are not diagnosed until they have reached an advanced stage. Putative precursor lesions are benign notochordal cell lesions, which are microscopically small and intraosseous. Different histologic chordoma subtypes differ in their prognosis. ^[3]

Microscopically, conventional chordomas are composed of uniform cells with small oval or round eccentric nuclei and dense chromatin. Hallmark microscopic features of chordomas include numerous, variably sized vacuoles located in the tumor cell cytoplasm and physaliphorous cells, as depicted in the images below. Some tumor cells may have more solid or eosinophilic cytoplasm.

Various histologic growth patterns can be seen in chordomas. Cells may be arranged in a diffuse or lobular pattern, or they may be clustered in groups or islands in a sheetlike pattern. Areas of tumor cells may be seen in a solid, perivascular, or even ribbonlike pattern. Between the cells or clusters, an abundant basophilic-to-metachromatic mucinous matrix exists. Mitoses, foci of pleomorphic cells, and focal hemorrhages are rarely seen but are not prominent features. Fibrous tissue surrounds the neoplasm and extends projections into the tumor, usually without forming a true capsule.

Poorly differentiated chordoma is a newly recognized entity in the World Health Organization (WHO) classification of tumors of soft tissue and bone. Slightly more than 60 such cases had been documented by the end of 2021. ^[19]  Poorly differentiated chordomas are more common among young adult and pediatric patients, as are skull base chordomas. Poorly differentiated chordomas show loss of the INI1 gene. ^[1]

Poorly differentiated chordomas display a spectrum of features, are associated with a lower index of suspicion for diagnosis, and involve aggressive outcomes. Critical analysis of radiologic and histopathologic features, including necessary immunostaining (brachyury and SMARCB1/INI1), is supportive of their timely diagnosis. These tumors show loss of SMARCB1/INI1 immunostaining and homozygous deletion of the INI1/SMARCB1 gene. ^[19]

In a case report, Curcio and coworkers suggested that loss of SMARCB1 is an early event in cases of rare conventional chordoma that could potentially evolve into poorly differentiated chordoma through additional genomic aberrations such as genome doubling. They concluded that further studies are needed to determine whether genome doubling provides a consistent pathway for evolution of poorly differentiated chordoma. ^[20]

Dedifferentiated chordomas typically are the fastest-growing and most aggressive chordomas; they can show loss of INI1 and are more common among pediatric patients. Chordomas have been reported to dedifferentiate into high-grade spindle cell tumors, which portend a worse prognosis. ^[1]  The dedifferentiated variant of chordoma is rare, accounting for 2-8% of chordomas. These can occur de novo or as a sarcomatoid transformation in recurrence of conventional chordoma, sometimes following radiation therapy. ^{[21, 22]}

The chondroid variant of chordoma is well recognized. With these tumors, a significant cartilaginous component is present, along with features of either chondrosarcoma or chondroma. Some investigators believe that these entities are separate and that studies with both immunoperoxidase staining and electron microscopy can distinguish them. Patients with this variant were once thought to have a slightly better prognosis; however, later, large studies have showed this variant to have no prognostic significance.

Chondroid chordomas are difficult to distinguish from chondrosarcomas on histology. Typically, chordomas express the gene brachyury, whereas chondrosarcomas do not express this gene. ^[1]  For chordoma, brachyury has been identified as a prominent biomarker and a potential molecular immunotherapy target, as well as a target of programmed death-1 (PD-1) inhibition. ^[23]

With specialized histochemistry, chordoma tumor cells tend to be periodic acid-Schiff (PAS) positive. The matrix stains diffusely with mucicarmine and Alcian blue, and it stains metachromatically with toluidine blue; it is negative with Sudan black.

On electron microscopy, ultrastructural features of chordoma include desmosomal attachments and prominent mucinous vacuoles.

Immunohistochemically, tumor cells label with cytokeratins and epithelial membrane antigen (EMA). Both chordomas and the embryologic notochord are S-100 positive, whereas most carcinomas are negative. This difference in S-100 positivity can be helpful in differentiating metastatic carcinomas from chordomas when the histologic pattern is similar. Positivity for cytokeratins and EMA can be helpful in distinguishing the chondroid variant of chordoma from chondrosarcoma.

Immunohistochemical and gene microarray studies have revealed the presence of high levels of brachyury in axial chordomas. Brachyury is a key transcription factor in the development of posterior mesoderm, which becomes restricted to the notochord and the tailbud. Although the classic marker—cytokeratin—remains the single best diagnostic marker for chordoma, brachyury added to the diagnostic panel slightly improves accuracy. ^[24]

Continuing research into the molecular pathophysiology of chordoma has led to the discovery of several pathways that may serve as potential targets for molecular therapy, including a multitude of receptor tyrosine kinases (eg, platelet-derived growth factor receptor [PDGFR], epidermal growth factor receptor [EGFR]), downstream cascades (eg, phosphoinositide 3-kinase [PI3K]/protein kinase B [Akt]/mechanistic target of rapamycin [mTOR]), brachyury—a transcription factor expressed ubiquitously in chordoma but not in other tissues, and the fibroblast growth factor (FGF)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Investigation and advances in the field may lead to improved outcomes for patients with this challenging disease. ^[10]

The role of MIB-1 immunohistochemical staining (a proliferation marker) as a prognostic indicator in chordoma is controversial, but data suggest that an increased MIB-1 labeling index correlates with recurrence.

Selection of molecular targeted inhibitors (MTIs) for patients with advanced or relapsed chordoma should be based on gene mutation screening and immunohistochemistry. Tyrosine kinase inhibitor (TKI) monotherapy is recommended as first-line management, and combination therapy (2 TKIs or 1 TKI plus 1 mTOR inhibitor) may be the choice for drug-resistant chordoma. Brachyury vaccine offers a promising therapeutic strategy; additional clinical trials are needed to evaluate its safety and efficacy. ^[25]

Cytologic detection of chordoma cells in the serosal cavity is challenging because of its rare presentation. Investigators reported the first case of chordoma showing malignant pleural effusion accompanied by pleuroplumonary metastases in a 68-year-old woman for whom chordoma cells were cytologically detected in pleural effusions. These findings suggest that conventional cytology combined with cell block immunocytochemistry can increase the accuracy of chordoma cell detection in the serosal cavity. ^[26]

An integrative analysis of clinicopathologic and molecular characteristics of dedifferentiated chordoma reported that by immunohistochemistry, the conventional/chondroid component consistently expressed cytokeratin and brachyury, whereas the dedifferentiated component showed loss of both. Further, a sacral conventional chordoma with INI1 loss was identified, with one of the lung metastases showing biphasic histology with loss of cytokeratin and brachyury in the dedifferentiated component. Sequencing revealed tumor suppressor mutations in 4 tumors, including TP53 mutations in the dedifferentiated component in 3 tumors. ^[27]

In summary, dedifferentiated chordoma involves diverse sites and presents de novo, post radiotherapy, or as recurrence/metastasis months to years after initial diagnosis. The dedifferentiated component shows loss of brachyury and cytokeratin staining and harbors recurrent TP53 mutations, implicating tumor suppressor dysregulation in chordoma dedifferentiation. ^[27]

Chordomas are localized in the axial skeleton, where they occur from the clivus to the sacrococcygeal region. They are slow-growing, locally destructive tumors that often are not diagnosed until they have reached an advanced stage. ^[3]

The inherent FDG avidity of chordomas suggests that ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) may be a useful modality for staging, evaluating treatment response, and assessing recurrent or metastatic disease. ^[28]

Age at diagnosis, tumor size, and disease stage can influence conditional survival for patients with chordoma. The hazard ratio of different factors changes over survival time. Therefore, understanding the changing risk profile and the conditional 5-year disease-specific survival (DSS) of chordoma is critical for accurate clinical treatment guidance. ^[29]

Patients receiving radiation therapy showed decreased survival—likely an indication of the patients' advanced stage of disease, making them poor surgical candidates. ^[15]