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Chordoma

Epidemiology

The true incidence of chordoma is unknown. In several large studies, it accounted for 1%–4% of all primary malignant bone tumors. In more recent data, collected by the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program, which included 12,931 primary malignant tumors of the bone diagnosed between the years 1973 and 2012, 8.3% or 1080 cases were chordoma, and chordoma followed osteosarcoma, chondrosarcoma, and Ewing sarcoma in frequency. Updated SEER data report an overall incidence rate of chordoma of 0.84 per 1,000,000. SEER data from the years 1973 to 2003 show that chordoma follows chondrosarcoma and accounts for 26% of primary bone malignancies of the spine in patients who present with a nonmetastatic primary bone malignancy. In a report from the Leeds Regional Bone Tumor Registry, chordoma was the most common primary malignant tumor of the axial skeleton. Information from the Swedish Registry documented the annual incidence of chordoma in that country to be 0.5% per million individuals and indicated that chordoma was responsible for 17.5% of all primary malignant bone tumors and 20% of those arising in the spine. Similar epidemiologic characteristics were found in Finland.

Chordoma occurs in all age groups, but the majority arises during adulthood, with the median age of affected individuals being 58 years and 65% of patients being younger than 65 years at the time of diagnosis. Specifically, children, young adults, adults, and the elderly have incidence rates of 0.14, 0.43, 1.08, and 2.62 per million population, respectively. Chordomas originating in the base of the skull present a decade earlier than those that develop in the spine, especially the sacrum. The occurrence of chordoma in children is unusual, representing <5% of all chordomas, but in our experience and from data in the literature, it usually originates in the skull base and cervical spine and rarely in the sacrum. Most studies of chordomas have shown that there is a male predominance of approximately 2:1 for tumors arising in the sacrum and mobile spine, whereas in the skull base, the gender distribution is nearly equal. In the SEER data, the vast majority of tumors arose in whites, whereas only 2.2% affected African Americans.

The pathogenesis of chordoma is not fully elucidated, but numerous lines of evidence suggest that T ( brachyury ), a gene that encodes brachyury, a transcription factor that regulates notochord development, is crucial for the initiation and progression of chordoma. Although it is generally accepted that these tumors arise from persistent rests of notochord within rigid bony structures, and not intervertebral disks, this hypothesis has never been proven. Evidence supporting this hypothesis linking notochordal cell rests to chordoma include similar topographical distribution, morphological overlap at the light and electron microscopic levels, shared immunophenotype, and molecular phenotyping studies. Chordoma has no known association with irradiation or other environmental factors. A very small percentage of cases have a familial pattern of inheritance, and in at least one case, the mode of inheritance was probably autosomal dominant. A subset of both sporadic and hereditary chordomas has somatic chromosomal gain at the T locus. In four families with familial chordoma, high-resolution array comparative genomic hybridization showed unique duplications in 6q27, leading to T gene duplication. A study sequencing the T gene and measuring copy number variants in 24 familial cases, 103 sporadic cases, and 160 unrelated controls highlighted the importance of genetic variations in the T gene for both familial and sporadic chordoma. It demonstrated that germline T duplication is relatively common in families with chordoma (44%) but extremely rare in sporadic cases and suggested a complex susceptibility related to T . Broad genotyping of individuals with sporadic chordoma has highlighted recurrent single nucleotide polymorphisms (SNPs) in the T DNA–binding domain, suggesting that misregulation of genes controlled by T may be important in the pathogenesis of chordoma. Pathways shown to be important in chordoma tumorigenesis include cell cycle regulatory pathways and activated receptor kinase pathways; additionally, DNA methylation of tumor suppressor genes and microRNA’s has been demonstrated to modulate relevant pathways (see Chapter 4 ).

The anatomic distribution of chordoma is largely restricted to the axial skeleton, and this is in keeping with the purported tumor origin from persistent notochord. The overwhelming majority of chordomas arise within bone; they have never been reported to originate in the intervertebral disk. Historical studies reported that approximately 50% of chordomas develop in the sacrococcygeal region, whereas more modern data with larger numbers of patients suggest an approximately even distribution of tumors between the sacral region, mobile spine, and sphenooccipital region. Within the mobile spine, one series of 40 cases showed that 48% of tumors arose in the cervical spine, 33% in the lumbar spine, and 17% in the thoracic spine.

Classification and Pathology

Pathologically, chordoma is classified into the conventional, chondroid, and dedifferentiated variants. A component of the conventional type is virtually always found in the chondroid and dedifferentiated variants.

Conventional Chordoma

Conventional chordoma grows with a lobular architectural pattern and grossly is soft, slimy, gray-tan, and well delineated from the surrounding soft tissues ( Fig. 2.1 ). The size of the tumors is variable, but the largest are usually found in the sacrum, where they frequently span greater than 10 cm in greatest dimension; the smallest typically arise in the skull base and may be only several centimeters in size. In bone, the tumor infiltrates the marrow space, encasing preexisting bony trabeculae, and permeates the Haversian systems of the cortex. Once the cortex is transgressed, the neoplasm usually extends into the soft tissues where it forms a well-demarcated soft tissue mass.

Chordoma arising in the sacrum, destroying the vertebral bodies, forming a large anterior soft tissue mass and extending into the spinal canal. The tumor is solid, glistening, and focally hemorrhagic.

Histologically, conventional chordoma is composed of lobules of cells arranged in cords and cohesive nests ( Fig. 2.2 ). It is common for one tumor cell to wrap around its neighbor as if one cell is “hugging” the other. Generally, the tumor cells are large, polyhedral, and epithelial in appearance and vary little in size and shape. The nuclei are of moderate size, darkly staining, and may contain small nucleoli or pseudoinclusions ( Fig. 2.3 ). The tumor cells have abundant pink cytoplasm, and some contain single, large or multiple, small, round, clear cytoplasmic vacuoles that impart a “bubbly” appearance to the cytoplasm ( Figs. 2.3 and 2.4 ). These vacuolated cells are known as physaliphorous cells , a term coined by Virchow in 1857 (derivation in Greek for “bubble-bearing”), and have since that time become recognized as characteristic of chordoma. Physaliphorous cells may also contain a single large, clear vacuole that displaces the nucleus peripherally, causing the cell to mimic an adipocyte—tumors with many of these cells have been called lipoid chordomas.

Chordoma composed of nests and chords of tumor cells that grow in a mucinous matrix.

Chordoma cell nuclei have identifiable nucleoli and the cytoplasm is abundant.

Physaliphorous cells containing multiple clear cytoplasmic vacuoles.

Because physaliphorous cells are not always present in chordomas and other types of tumors, including chondrosarcoma, may have similar appearing cells, their diagnostic significance is limited. Additional morphological heterogeneity in otherwise conventional chordomas includes cells that demonstrate nuclear pleomorphism, and sometimes the cells are elongate and spindle shaped. Special histochemistry demonstrates that the neoplastic cells contain periodic acid–Schiff-positive diastase-sensitive glycogen. Ultrastructurally, the neoplastic cells have cytoplasmic processes that wrap around an adjacent cell, villous-like surface projections, abundant cytoplasmic glycogen, mitochondria-rough endoplasmic reticulum complexes, and epithelial features, including well-developed desmosomes, intracytoplasmic lumina, and tonofilament-like bundles of intermediate filaments. The vacuoles of the physaliphorous cells do not stain with any of the special stains, and according to ultrastructural analysis, they may be formed from dilated rough endoplasmic reticulum, cytoplasmic inclusions of the extracellular space, or intracellular lumina.

Immunohistochemically, conventional chordoma typically expresses the epithelial markers keratin and epithelial membrane antigen, and the vast majority also stain with antibodies to the calcium-binding protein S-100. Immunohistochemistry for brachyury has emerged as a highly sensitive and specific marker for chordoma.

In most conventional chordomas, mitoses are usually limited in number and foci of necrosis are common, especially in large tumors.

The stroma in conventional chordoma is usually mucinous and myxoid and typically appears frothy and basophilic. It is usually abundant and surrounds the cords and nests of cells ( Fig. 2.2 ). The myxoid stroma is rich in acid and sulfated mucopolysaccharides and stains faintly with mucicarmine, strongly with alcian blue, and not at all with phosphotungstic acid hematoxylin. Staining of the matrix is not significantly reduced by prior digestion with hyaluronidase.

Chondroid Chordoma

Chondroid chordoma was identified as a clinicopathological entity in 1973. It was defined as a tumor that contained areas of conventional chordoma as well as regions that resembled low-grade hyalinetype chondrosarcoma. In the initial description, the clinical significance of chondroid chordoma was that affected patients had a better prognosis than those with conventional chordoma. Following its description there was controversy regarding the existence of the tumor because some investigators argued that it merely represented a form of chondrosarcoma. Subsequently, several studies have convincingly shown that chondroid chordoma is a distinct morphological variant of chordoma, does not behave biologically differently from conventional chordoma, and is not a chondrosarcoma. The initial studies suggesting that chondroid chordoma had a better prognosis than conventional chordoma may have been impacted by the inclusion of some chondrosarcoma cases in the chondroid chordoma cohort.

Chondroid chordoma most commonly arises in the skull base, less frequently in the mobile spine, and seldom in the sacrococcygeal area. Morphologically, the chondroid regions may merge with or be sharply demarcated from the classic component ( Fig. 2.5 ). The chondroid component is characterized by neoplastic cells arranged individually in lacunar spaces that are surrounded by a solid, hyalinized matrix similar in appearance to the matrix in hyaline cartilage ( Fig. 2.5 ). The amount of the chondroid component can vary, and in some cases, it may be abundant, causing diagnostic confusion with chondrosarcoma. The chondroid element has the same ultrastructural features and immunohistochemical profile as the conventional component ( Fig. 2.6 ). Accordingly, the chondroid tissue represents a change in the matrix and distribution of cells in a chordoma that causes it to mimic hyaline cartilage and, importantly, does not represent true hyaline cartilage.

Chondroid chordoma containing foci of conventional chordoma with adjacent chondroid regions in which the tumor cells are individually arranged in lacunar spaces in a more solid hyaline appearing matrix.

Immunohistochemistry of chondroid chordoma showing that the cells in the conventional and chondroid areas strongly express keratin.

Cytogenetics

Cytogenetic analysis of chordoma has shown numerous cytogenetic abnormalities. To date, no tumor-specific rearrangements have been documented. Most cytogenetically interrogated chordomas show several numerical and structural rearrangements in the setting of near-diploid or moderately hypodiploid karyotypes. Frequent aberrations include partial or complete loss of chromosome arms 1p, 3p, 4q, 10q, and 13q, and partial or complete gain of material from chromosome arms 7p, 7q, 12q, 17q, 20q, and 22q. Loci that are frequently deleted or amplified include 1p36 (containing the RIZ locus that encodes a zinc finger protein and the RUNX3 locus that encodes a transcription factor), 1p25 ( HPC1 , hereditary human prostate cancer susceptibility locus), 2p13 (the TGF-alpha , transforming growth factor-alpha locus), and 7q33 (the AKR1B10 locus, encoding an aldo-keto reductase). Additionally, the CDKN2A and CDKN2B loci on chromosome 9p21, encoding cyclin-dependent kinase inhibitors p16 and p15, respectively, are deleted in up to 70%–85% of tumors, PTEN on chromosome 10q in 80% of tumors, and SMARCB1 on chromosome 22q in 75% of tumors. Genome-wide high-resolution SNP array and next-generation sequencing studies on 16 cases of sporadic chordomas found that chordomas frequently exhibit nonrandom gene copy number losses across the genome (chromosomes 3, 9p, 1p, 14, 10, and 13) and that the mutation rate is low, with the mutated genes often targeting chromatin regulatory genes. The gene most frequently affected by either deletion or mutations is SETD2 . The recently described mechanism of chromothripsis, the shattering of chromosomes in a single catastrophic event followed by recombination leading to tens to hundreds of genetic rearrangements involving localized genomic regions, has been implicated as a causal mechanism for genetic rearrangements in chordoma.

Prognostically and Therapeutically Significant Pathological Features

The prognosis of chordoma is affected by a variety of pathological characteristics. Several reports have suggested that the proliferative rates of chordoma cells as measured by MIB-1 may be helpful in identifying those tumors at greatest risk for local recurrence and shorter overall survival. Similarly, tumors with increased expression of proliferating cell nuclear antigen expression have been correlated with shorter continuous disease-free survival. Loss of heterozygosity in the retinoblastoma tumor suppressor gene was found in two of seven skull base chordomas, and these two tumors behaved aggressively. Studies examining p53 protein expression in chordoma have demonstrated inconsistent correlations with prognosis. The presence of chondroid regions, the degree of cellularity, the cytologic features of the tumor cells, DNA ploidy status, and the staining reaction to silver of the nucleolar organizing region have not been shown to have any prognostic significance.

Several studies have shown that skull base chordomas in young children frequently have atypical histological features and an aggressive clinical course, particularly in children younger than 5 years. A study of 73 skull base chordomas in children showed that 58% were conventional chordoma, 23% chondroid, and 19% demonstrated unusual histology. The tumors with unusual histology did not fit the criteria for conventional, chondroid, or dedifferentiated chordoma and have sometimes been labeled in the literature as atypical chordoma ; the authors further defined the specific atypical histological features and designated 11% as cellular chordoma and 8% as poorly differentiated chordoma . Tumors composed of cells with conventional cytologic features of chordoma including physaliphorous cells but lacking extracellular matrix define cellular chordoma, whereas poorly differentiated epithelioid tumor cells in a fibrous stroma lacking physaliphorous cells characterize poorly differentiated chordoma. In this study, all but one patient with poorly differentiated chordoma died of disease, whereas the overall cohort survival rate was 81% with a mean follow-up of 7.25 years, characterizing poorly differentiated chordoma as a highly aggressive tumor.

Although alkylating agents, alkaloids, and related therapies may have a modest effect on dedifferentiated chordoma, no effective chemotherapeutic agents are available for treatment of most chordomas. However, targeted molecular therapies are emerging as possible treatment options. Overexpression of constitutively active phosphorylated platelet-derived growth factor receptor (PDGFR)-B, PDGFRA, and of KIT receptors within chordoma has prompted treatment with tyrosine kinase inhibitors such as imatinib and sunitinib with some success. The epidermal growth factor receptor (EGFR) pathway has also been implicated in chordoma development, and EGFR inhibitors such as erlotinib, gefitinib, and cetuximab have been utilized in a limited number of patients. A topoisomerase I inhibitor, 9-nitro-camptothecin was used in a small number of patients and appeared to slow disease progression. Other therapies that have been attempted in a limited number of patients include vascular endothelial growth factor and mammalian target of rapamycin inhibition. A systematic review of 19 publications (January 1990 to September 2014) regarding molecular targeted therapy for chordoma found that the best objective response was stabilization of disease in 52%–69% of chordomas. To date, no randomized clinical trials have been performed in this regard, and consequently it is unclear whether the disease stabilization effects are direct results of molecular targeted therapy or whether some disease stabilization is inherent to the natural history of chordoma as a generally slowly growing tumor. Preliminary evidence suggests a role for the activation of phosphorylated signal transducer and activator of transcription 3 (STAT3) in chordoma, a transcription factor implicated in several human malignancies and associated with poor prognosis, and there is some in vitro evidence that STAT3 inhibits chordoma cell growth and proliferation. One study of 40 skull base chordomas showed that increased protein expression by immunohistochemistry of components of the bone morphogenetic protein 4/SMAD signaling pathway was associated with larger tumor size, presence of dural invasion, and decreased 5-year overall survival rate. Emerging data document the overexpression of programmed death-1 receptor (PD-1) and its ligand, PD-L1, in chordoma tumors and tumor-infiltrating lymphocytes (TILs), raising the possibility for immunotherapeutic approaches to chordoma treatment. Higher PD-L1 expression in chordoma tumors appears to correlate with more advanced stage and increased presence of TILs. In one study, PD-L1 expression in TILs appeared to be an independent predictor for recurrence-free and overall survival in spinal chordomas.