Pathology

Chordomas are very rare bone tumors. Data from the early 2000’s shows that their incidence rate is 0.1/100,000/year. Median age of presentation is 60 years. Unfortunately, skull base chordomas affect younger age groups. Although not common, they may occur in children and adolescents. ¹ Their specific predilection for the axial skeleton presents as the most common locations being the sacrum, skull base, and remaining sites of the spine, respectively. Most recent molecular data evidently support that these uncommon tumors stem from embryonic rests of the notochord and show a dual epithelial–mesenchymal differentiation. ² Clinically, they are locally invasive, aggressive tumors showing a downhill course. Their morphological subtypes are classic (conventional), chondroid, and dedifferentiated (sarcomatous). Although there are some conflicting reports, it is generally accepted that the chondroid variety has a more favorable prognosis in comparison with other varieties. Although exceptional, these tumors have the potential to metastasize to visceral organs, lung and liver, and other extra-axial skeleton. Like the slowly progressing main tumor, its metastases indolently grow. It is not surprising to find local recurrences in those patients who were followed longer than a decade. ³

7.2 Epidemiology

Chordoma is a rare cancer that accounts for 1 to 4% of all bone malignancies. ⁴ Although histologically considered to be a low-grade neoplasm, chordomas are highly recurrent, making their clinical progression very similar to that of malignant tumors. ⁵^,⁶ Population-based studies using the Surveillance, Epidemiology, and End Results (SEER) database suggest an incidence of chordomas of 0.08 per 100,000, with predominance in men and peak incidence in patients between 50 and 60 years of age. ⁷ Chordomas have very low incidence in patients younger than 40 years, and rarely affect children and adolescents (< 5% of all chordomas cases). ⁷^,⁸ The most comprehensive survival analysis, involving assessment of 400 cases from the SEER database, showed a median survival of 6.29 years with 5-, 10-, and 20-year survival dropping precipitously to 67.6, 39.9, and 13.1%, respectively, across all races and both sexes. ⁷ These slowly growing tumors are derived from remnant notochord occurring anywhere along the central neural axis. In the adult, an estimated 33 to 37% is located at the skull base. ⁹^,¹⁰^,¹¹^,¹²

7.3 History

Chordomas were first characterized microscopically by Virchow in 1857. ¹³ He described unique, intracellular, bubble-like vacuoles that he referred to as physaliphorous, a term now synonymous with their histopathology. These physaliphorous features of chordomas remain a distinguishing, if not pathognomonic, feature. Virchow hypothesized that chordomas were derived from cartilage; however, more contemporary evidence suggests that they are derived from undifferentiated notochordal remnants that reside within the vertebral bodies and throughout the axial skeleton. ¹⁴ In fact, Ribbert first introduced the term chordoma in the 1890s, in view of the notochord hypothesis. ¹⁵ Examination of human embryos and fetuses ¹⁶^,¹⁷^,¹⁸^,¹⁹ and cell fate–tracking experiments in mice ²⁰ showed that notochordal cell rests topographically correspond and distribute to the sites of occurrence of chordomas. Although there is not much direct evidence that cells transform to chordomas, molecular phenotyping of these primitive rests compared with neoplastic lesions suggests that they are indeed the likely source for transformation. ¹⁸^,¹⁹

In 1973, Heffelfinger and colleagues described chordomas that contained hyaline-type chondroid or cartilaginous tissue, with tumor cells residing within lacunar spaces. ²¹ The amount of this cartilaginous matrix varied from tumor to tumor, with some having a predominance of chordomatous tissue and others an equal amount of both elements, and in a smaller number of cases, the cartilaginous foci predominated such that the lesion was indistinguishable from either chondroma or chondrosarcoma, with only focal regions of conventional chordomas being present. The authors designated such a cartilage-containing chordomas as a chondroid chordomas. In the English literature since 1993, there are 54 cases so far. Almost all such tumors occur in the spheno-occipital region ²²; only a few examples have been reported in the spinal column, including the cervical, ²³^,²⁴^,²⁵^,²⁶^,²⁷ thoracic, ²⁸ and lumbar spine. ²⁹

7.4 Origin

Morphological, immunohistochemical, and ultrastructural features of the notochord, ecchordosis, and chordomas surprisingly bear precise similarities. Ultrastructural features of a 9-day embryonic chick notochord and the human chordomas most likely prove the derivation of the ecchordosis and chordomas from notochordal rests. ³⁰ Perhaps the most compelling evidence of the notochordal hypothesis was the discovery of gene duplication in the transcription factor T gene (brachyury) in familial chordomas. ³¹ An important transcription factor in notochord development, brachyury is expressed in normal, undifferentiated embryonic notochord in the axial skeleton. ¹⁸^,¹⁹ High-resolution array comparative genomic hybridization showed unique duplications in the 6q27 region in tumor samples from patients with familial chordomas. ³¹ This duplicated region contained only the brachyury gene, which was known to be uniquely overexpressed in almost all sporadic chordomas compared with other bone or cartilaginous lesions. ¹⁸^,³² Brachyury regulates several compelling stem cell genes and has been implicated in promoting epithelial–mesenchymal transition in other human carcinomas. ³³ Although it is still unclear what role brachyury has in the pathogenesis of chordomas, identification of the duplication and the remarkable overexpression seen in samples suggest that it might be a crucial molecular driver in the initiation and propagation of chordomas.

7.5 Gross Findings

Chordomas can be firm to semiliquid with a lobulated, gelatinous appearance and focal calcifications. Its margin can be expansile or infiltrative.

7.6 Microscopic Findings

Chordomas are composed of lobules of large, polyhedral cells arranged in sheets and ribbons and separated by abundant mucinous ground substance. Their cytoplasm bears vacuoles in different size and shape. The eye-catching, vastly vacuolated cells are termed “physaliphorous” (Greek for “bubble-bearing”) ( ▶ Fig. 7.1). The other three cell types are smaller cells with nonvacuolated cytoplasm, stellate cells, and intermediate forms. Histochemically, two distinctive mucinous material types are found, neutral and acidic mucopolysaccharides, where the former type is merely located in cytoplasmic vacuoles and the latter is abundant in the tumor matrix ( ▶ Fig. 7.2).

Fig. 7.1 The finding of vacuole-bearing, so-called “physaliphorous,” cells is a hallmark of chordomas. These cells are marked by intracytoplasmic droplets of mucinous material and are also typically embedded in a mucin-rich extracellular matrix. This is most likely a homologue of the notochordal remnant cells with large vacuolated cytoplasms expressing epithelial markers that may be found in the normal adult nucleus pulposus.

Fig. 7.2 As it is evident in this Alcian blue–periodic acid–Schiff (PAS)–stained preparation, acidic mucinous material is very commonly encountered in chordomas.

Chordomas exhibit several degrees of histologic atypia, and the association between histopathologic properties and biological behavior remains a vigorous and contentious area of ongoing studies ( ▶ Fig. 7.3). Chordomas, as a group, display one of three histologic variants: classic (conventional), chondroid, or dedifferentiated (sarcomatous). ³⁴

Fig. 7.3 The histomorphological findings may be quite variable in chordomas and physaliphorous cells containing giant vacuoles or moderately atypical cells are not uncommon in chordomas and are not necessarily indicative of malignant behavior.

7.6.1 Classic Chordomas

Classic chordomas appear as soft, tan, and lobulated tumors consisting of groups of cells separated by delicate fibrous septa. ³⁴ The so-called physaliphorous cells are polyhedral with eosinophilic cytoplasm and, typically, with many small vacuoles displacing the nucleus that are arranged in cords, trabeculae, or sheets in a myxoid matrix ( ▶ Fig. 7.4).

Fig. 7.4 The characteristic physaliphorous cells of chordomas with their eosinophilic cytoplasms, bearing small vacuoles, may be are arranged in cords, trabeculae, or sheets in a myxoid matrix.

7.6.2 Chondroid Chordomas

The second variant of chordoma is chondroid chordomas, which consists of a mixture of the typical chordomas and areas that resemble cartilage. After its description in 1973, until now, 54 cases have been reported in the English literature. Although it occurs mainly in the spheno-occipital region, there are cases located in the sacrococcygeal region, ³⁵ temporal petrous bone, ³⁶ thoracic spine, ²⁸ lumbar spine, ²⁹ and intrasellar ³⁷ and intradural suprasellar ³⁸ Upon meticulous analysis of the articles, some conflicting histologic properties of this tumor were found. Its original description profoundly emphasizes chordoma with cartilaginous islands ²¹ ( ▶ Fig. 7.5). There are cases where some of the tumors show chordomatous dominance and others with cartilaginous dominance, and some other show biphasic pattern compatible with a true mixed tumor. ³⁹^,⁴⁰ Therefore, due to lack of a precise definition of chondroid chordomas, overall survivals vary, most likely because some chondrosarcomas with dominant chordoid-resembling areas might be diagnosed as chordomas or vice versa. Hitherto, there is no consensus on a precise description of chondroid chordomas based on characteristic morphological, immunohistochemical, and molecular biomarkers. ⁴¹

Fig. 7.5 The “chondroid” variant of chordomas was initially described by Heffelfinger et al in 1973. Cartilaginous differentiation is a hallmark of this morphological variant. Whether this subtype is associated with a different clinical course is still debated.

7.6.3 Dedifferentiated Chordomas

The third type, dedifferentiated chordomas, displays a sarcoma-like morphology, that is, fibrosarcoma, ³⁹ malignant fibrous histiocytoma ³⁹ ( ▶ Fig. 7.6), osteosarcoma, ³⁹ or rhabdomyosarcoma. ⁴²^,⁴³ This unusual type of chordoma might present “ab initio,” or might appear in recurring chordomas or in metastasis. ⁴¹ These tumors are called “dedifferentiated chordomas” by analogy to dedifferentiated chondrosarcomas. They have a lethal clinical course, and almost 90% of these tumors develop metastases. ⁴¹

Fig. 7.6 The morphology of this specimen of dedifferentiated chordomas, which is from a previously irradiated chordoma patient at the second recurrence, is marked by pleomorphism and hypercellularity, marking this a “dedifferentiated chordomas.” The histopathology mimicks a malignant fibrous histiocytoma.

7.7 Electron Microscopic Findings

Chordomas contain cells that resemble those of the developing notochord and ecchordosis. ⁴⁴ Ecchordosis cells demonstrate glycogen-laden intracytoplasmic vacuoles, focally distended endoplasmic reticulum and perinuclear cisterns with cytoplasmic invaginations, large clusters of granular endoplasmic reticulum interdigitating with mitochondria, and an abundant extracellular space. ¹⁵ Chordomas bear three distinctive cell types: large, mononucleated or binucleated physaliphorous cells with a vacuolated “bubbly” cytoplasm; small, rounded, uniform cells; and short, spindle-shaped cells. ⁴⁵ The largest part of the cells show the presence of tonofilaments, a well-developed Golgi apparatus, intermediate filaments, a dilated rough endoplasmic reticulum, desmosomes, abundant cytoplasmic glycogen, alternating arrays of mitochondria, pinocytotic vesicles, subplasmalemmal linear densities, and parallel arrays of crystalline structures of microtubules within the endoplasmic reticulum. ⁴⁶ Though not very common, there might be parallel bundles of criss-crossing ⁴⁷ and aggregates ⁴⁸ of microtubules within the rough endoplasmic reticulum. The large vacuoles and lumina often are bordered by microvillous projections, whereas cells are connected to one another by well-developed desmosomes. ⁴⁵ The cytoplasmic vacuoles consist of either dilated endoplasmic reticulum or, in physaliphorous cells, cytoplasmic invaginations or herniations of extracellular interstitial material.

Although intraergastoplasmic tubular structures are more common in chondroid chordomas than in typical chordomas, they are not a definitive distinguishing feature. ⁴⁹ But chondroid chordomas have somewhat fewer desmosomes and intermediate filaments as compared with typical chordomas. ⁵⁰

7.8 Cytological Findings

Chordomas have three distinctive cell types as described in Electron Microscopic Findings. The May-Grünwald-Giemsa staining was found superior to Papanicolaou staining in demonstrating the mucoid matrix and the vacuolated cytoplasm of the physaliphorous tumor cells. ⁴⁵

7.9 Immunohistochemical Findings

Chordomas were identified by their physaliphorous features and immunoreactivity for S100 ( ▶ Fig. 7.7), epithelial membrane antigen (EMA) ( ▶ Fig. 7.8), and cytokeratins ²²^,³⁹^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷ ( ▶ Fig. 7.9). Keratins 8, 13, 15, 18, and 19 and HMBE-1 are selectively expressed in chordomas ⁵⁸^,⁵⁹^,⁶⁰; 30 to 90% of them express the S100 protein. ²²^,⁶¹^,⁶² HMBE-1 is a monoclonal antibody recognizing an unknown antigen on mesothelial cells, and neuroendocrine markers reacted strongly with chordomas and skeletal chondrosarcomas. ⁶¹

Fig. 7.7 The S100 protein is a marker for epithelial differentiation and is therefore very frequently positive in physaliphorous cells of chordomas along with other epithelial markers such as EMA and cytokeratin. This is an example of chordomas with marked nuclear and cytoplasmic reactivity for S100.

Fig. 7.8 Chordomas cell membranes are frequently reactive with the epithelial membrane antigen (EMA), which is a standard marker for epithelial differentiation.

Fig. 7.9 Tumor cells in chordomas also display strong cytoplasmic reactivity for various cytokeratins. This is an example staining with the pan-cytokeratin antibody.

Galectin-3 has been implicated in several biological processes, including tumor progression, apoptosis, and metastasis. ⁶³^,⁶⁴ Galectin-3 is expressed in the primitive notochord and is positively reacting in 75% of chordomas, whereas it is mildly reactive in chondromas. ⁶⁵ Therefore, it is believed to be a sensitive but not a specific marker for distinguishing chordomas. ⁶⁵^,⁶⁶

Brachyury, a transcription factor crucial for notochordal development, is a sensitive and specific marker for chordomas. ¹⁸ Several groups have postulated that the notochord developmental transcription factor brachyury could be a novel discriminating biomarker for chordomas. ⁶^,¹⁸^,¹⁹^,³²^,⁶⁷^,⁶⁸ This hypothesis was validated with a tissue microarray-based analysis that assessed 103 skull base and head and neck chondroid tumors. ⁶⁷ The investigators identified brachyury as a discriminating biomarker of chordomas, and when combined with cytokeratin staining, sensitivity and specificity for detection of chordomas were as 98% and 100%, respectively. ⁶⁷ Brachyury staining to discriminate chordomas from other chondroid lesions has become integral in the pathologic work-up during diagnosis. CD24 is a cell adhesion molecule, a glycoprotein, and is expressed by the notochord-derived nucleus pulposus. ⁶⁹ CD24 is selectively expressed in chordomas. ⁶^,⁶⁷

YKL-40 (human cartilage protein 39 or CHI3L1) is a secreted glycoprotein that occurs ubiquitously in normal adult human tissues and its exact function has not been identified. ⁷⁰^,⁷¹ During fetogenesis, YKL-40 acts as a growth factor for chondrocytes and fibroblasts, showing varied expressivity in various phases of bone and joint formation. ⁷¹ Chordomas display variable YKL-40 reactivity, which is known to be a “high-activity” marker. ⁷⁰

Fibronectin is the glycoprotein found in the basement membrane and extracellular matrix and binds to integrins. ⁷² Chordomas express basic fibroblast growth factor, transforming growth factor-α, and fibronectin, which are correlated with local recurrence and aggressive biological behavior. ⁷³

Most spinal chordomas show high platelet-derived growth factor receptor-α (PDGFR-α reactivity, and even higher expressivity in recurrent tumors. High levels of PDGFR-α and c-MET reactivity are associated with younger age. Also, higher PDGFR-α expressivity is correlated with higher epidermal growth factor receptor (EGFR) expressivity in spinal primary and recurrent chordomas. ⁷⁴

EGFR (HER1) is a transmembrane protein receptor of the type I growth factor family with tyrosine kinase activity. ⁷² In recurrent chordomas, higher EGFR expressivity was found to be associated with poorer prognosis than with mild EGFR expressivity ⁷⁵ ( ▶ Fig. 7.10). Genes that are up-regulated in chordomas include CD24, EGFR, keratins 8, 13, 15, 18, and 19, and brachyury. ⁶ Chordomas express EGFR and c-MET and show strong expression of both. ⁷⁶^,⁷⁷ PDGFR-α (100%) and EGFR (67%) are detected in chordoma cases. ⁷⁸ Another study showed a high correlation between c-MET and EGFR expression in addition to that between PDGFR-α and c-MET expression in spinal chordomas. ⁷⁴