Electronic ISSN 2287-0237

VOLUME

CHORDOMA MANAGEMENT: A REVIEW OF THE LITERATURE

FEBRUARY 2019 - VOL.15 | REVIEWS ARTICLE

Chordoma is considered to be a rare low-grade malignant tumorof the spine occurring in only 1-4% of all malignant skeletaltumors.1 The reported incidence of chordoma is quite low (only0.08 per 100,000 pop). More males than females are affected as aremore Caucasians and Hispanics than African-Americans.2 The peakincidence of chordoma occurs in the fifth decade of life (50-59 years),and the incidence is very low in patients under the age of 40.2-4 A totalof only three hundred patients are newly diagnosed annuallyworld-wide.2,5 The median survival time is about 6 years, and thesurvival rate drops each year.2 The 10-year survival rate of chordomapatients is about 40%.2

While the distribution is almost equal in the sacrum, skull base,and vertebra,2 Chordoma is involved in most of the primary bone tumorsof the sacrum.6 Chordoma generally differs from others malignant tumorsin that it is a slow growing neoplasm, although it is locally invasive andaggressive. At the time of diagnosis, the tumor is generally in anadvanced stage, i.e., usually large, impinging on surrounding structures,and with poor margination, which makes Chordoma difficult to treatwith gross total resection and radiation. The rate of local recurrence isusually high despite the best initial management efforts.

In this article, emphasis is on recent choices of recently developedoptions for treatment and management of chordoma including radiationtherapy and molecular-targeting agents.

Chordomas are slow-growing tumors with no or very mildsymptoms until the late stage. The clinical presentations of chordomasare different depending on their location.7 Skull-based chordomas oftengrow in the clivus, so initial symptoms are headache and diplopia. Ifthe disease progresses without treatment, the clinical symptoms caninclude cranial nerve palsy, visual disturbance, or weakness. If thechordoma involves the sella, endocrinopathy may be present. Forchordomas of the sacrum and spine, initially, patients usually present with deep local pain, radiculopathy, bowel or bladder dysfunction,or even sexual dysfunction. When the disease progress, thetumors are sometimes palpable externally or during per rectalor vaginal examination.8, 9 Chordomas of the sacrumgenerally involve the 4th and 5th level of sacral vertebrae.When the neoplasm progresses, and becomes large, it cansometimes extend into the pelvic cavity, although the presacralfascia protects the pelvis from tumor invasion. Chordomas ofthe cervical spine, however, can initially present with upperairway obstruction or dysphagia; sometimes the patient willseek medical attention for a mass around the cervical or oropharyngealarea, depending on the tumor location.

In radiographic studies, chordomas typically appear asa destructive lesion that affects the axial skeleton and areassociated with a large soft tissue mass at the epicenter of thetumors within the vertebral body. Chordomas are unlikeosteosarcoma and chondrosarcomas of the vertebral body asthese are more often found in the appendicular skeleton.Chordomas usually extend locally into the intervertebral discspace, and finally spread to adjacent vertebra8 (Figure 1). Incomputed tomography (CT) scans, chordomas commonlyappear as an osteolytic, or mixed osteolytic and osteoscleroticbone lesion which usually has a myxoid component. The viewof chordomas can be enhanced with intravenous contrastinjection. With magnetic resonance imaging images (MRI),chordomas appear to be hyperintense on T2- weighted images,but range from isointense to hypointense on T1-weightedimages. Chordoma can also be enhanced with gadoliniumcontrast (Figure 2-3).

Distant metastases generally present in the late stage ofchordomas and usually are not presented at the time of initialdiagnosis for the reasons described earlier. The incidence ofchordomas which show distant metastatic at the time of initialpresentation has been reported to be only 5%. The most commonsites of distant metastases are lung, bone, skin, and brain. Inthe very late stage, the metastasis rate is as high as 65%.10,11

Case Example

A 45-year-old female presented with chronic low backpain for 5 years. Magnetic resonance imaging (MRI scan)shows a large mass located at the sacrum with T1-hypointensityand T2-hyperintensity with wall enhancement (internal septa)(Figure 2-3)

 

Figure 1: A: Film sacrum AP, B: Film lateral, the mass was accidentally palpated during an annualgynecological examination. From plain radiographs showing a large soft tissue mass with extensiveosteolytic lesion with its epicenter at the sacrum.

 

Figure 2: Show T-1 weight MRI, A: coronal view, B: saggital view

 

Figure 3: Show T-2 weight MRI, A: coronal view, B: saggital view

 

 

Figure 4: Specimen of chordoma from en bloc removal.

 

Figure 5: Chordoma histology showing large lobulatedtumor cell nests including sheets and elongated cords of clearcells with intracytoplasmic vacuoles, called physaliphorusor “soap bubble” cells in the area of the myxoid matrix

Reports have indicated that chordomas may arise fromnotochordal remnants which remain in the vertebra. They canoccur along the midline of the spine through the axial skeletalbone from the skull base to the sacrum.12 Histologicalstudies of chordomas are very similar to studies in thenotochord in that both consist of large lobulated tumor cellnests and include sheets or elongated cords of clear cells withintracytoplasmic vacuoles, called physaliphorus or “soapbubble” cells in the area of the myxoid matrix13 (Figure-5).

A recent study of chordomas showed the evidence ofsimilarities between chordomas and notochord which bothhave including a strong genetic relationship.14 The Brachyuryprotein, which is encoded by the T gene, is located onchromosome 6q27. Duplications or amplifications of the Tgene have been found to be closely associated with familialand almost all sporadic chordomas when compared withother bone neoplasm. The relationship between the T gene,Brachyury protein, and chordomas is still unclear and needsmore research, although, it is believed that the Brachyury genemight be an important initiator of this type of tumor.

A recent study of chordomas showed that there is asignificant connection between notochord gene and chordomas.The T gene, located on chromosome 6q27, encodes the Brachyuryprotein.14 A study of familial chordomas reported thatduplications of the T gene in family members will increasesusceptibility to chordomas. Furthermore, in the mostsporadic cases, an over-expression and amplification of thisgene when compared with other bone or cartilaginous lesionshas been reported.15-17 Although the role of the Brachyuryprotein in the pathogenesis of chordomas is still unclear,identification of the duplication and amplification of the T geneand its significant overexpression have been seen in thesestudies.

Many studies have tried to demonstrate prognosismarkers and one of the recent studies show SNF5 which isobserved in cytoplasm. The study investigated the relationshipbetween SNF5 and clinical features in skull base chordomaand found that low SNF5 expression is correlated with poorprognosis including progression free survival (PFS) andoverall survival (OS).18 Platelet-derived growth factorreceptor–b (PDGFR-b) is one of the prognostic markers thathas been recently reported. Higher expression level ofPDGFR-b in chordoma also correlated with poorer prognosisfor clival chordoma patients. PDGFR-b could regulate invasionthrough the mTOR pathway in clival chordoma cells.19

The treatment of chordomas is complicated and is stillcontinuously evolving. The need for comprehensivemultimodality treatment has been increasing in recent yearsincluding; 1) Expert surgeons, 2) Radiotherapy team. Recentretrospective cohort studies show the initial treatment in amultidisciplinary center resulted in a significant improvementin patients-free-survival (PFS) and reduction in the risk ofrecurrence.20 Although chordoma is classified histologicallyas a benign neoplasm, chordomas are locally invasive and havea high recurrence rate. These factors make prognosis as abenign neoplasm unlikely.9,21 Additionally, radiation therapyis still limited due to the lower tolerance of the spinal cord andbrain stem to the dose needed for clinically effective treatmentof the tumors.22 The use of radiotherapy as a primary treatmenthas proven to be not as effective as debulking surgery.23 Asystematic review reported that chordomas are insensitive toconventional chemotherapies because of their slow rate ofgrowth and their low cellular turnover rate.24 For all of thesereasons, the gold standard for chordomas management isusually extended resection with wide tumor-free margins.24However, en bloc surgical resection, introduced by Stener andGunterberg25 in 1987, has become a standard treatment forsacral chordomas. That operation can be challenging becausealmost all patients are diagnosed at the late stage and becauseof the invasion of surrounding tissue including vital neuralstructures with poor margination.25 As a result, partial resectionis often the only option, although it can lead to significantresidual tumor, tumor seeding, and finally recurrence of thetumors, although more aggressive and wider surgical marginshave proved to significantly decrease local recurrence ofchordomas.26,27 A study of surgical management of chordomasshowed a significant difference in outcomes between radicaland subtotal resection. The average time to local recurrencein patients who underwent subtotal resection was 8 monthscompared with 2.27 years for those who had radical resectionof chordomas.28 The complications seen after surgery varydepending on the area of the tumor involvement. Sacrectomiesthat resect the S2 nerve root are associated with abnormalbowel and bladder function (up to 50%). The percentage ofbowel and bladder involvement increases if the S3 nerve rootis also resected.29 Even though the best option for treatmentof recurrent chordoma is en bloc resection with negativesurgical margin, it is often difficult to perform in cases ofmultifocal disease. In those cases, limited resection should beconsidered to prevent disease progression as well as to preservefunction and avoid additional morbidity. For palliativetreatment, there are many options other than resection, e.g.,radiofrequency ablation (RFA), cryotherapy, low-dose RT andjust continued observation. Good candidates for completere-resection are patients with a single recurrent tumor, a longdisease free interval, and otherwise in overall good health.Patients who have not received radiation therapy either beforeor after primary surgery should be considered for radiationtherapy.30

Some studies suggest that radiation therapy in combinationwith surgical treatment can provide additional advantages.However, conventional radiation therapy with a high dose ofradiation can cause a variety of side effects. Common sideeffects such as myelopathy can occur due to radiation overdosebecause the spinal cord and the brain stem are more sensitiveto radiation than the tumor. It is not possible to provideappropriately administered clinically effective doses of radiationwithout causing radiation side effects. Newer methods ofradiation using hadrons i.e., high-dose of protons or chargedparticles, including carbon ions, helium, and neon, have beenintroduced. With these new technologies, it is possible to givehigher doses of radiation and to achieve more effective tumorradiation therapy with less severe side effects on surroundingstructures.31-33 The heavy ions such as those in hadron-basedtherapy provide more benefit compared with photon radiation,their biological effectiveness is relatively higher, and they canreduce the oxygen enhancement ratio in the tumor area.Carbon-ion radiation therapy has been recently introduced formanagement of advanced chordomas which are unresectable.34A retrospective study showed that carbon-ion radiation canlower local tumor recurrence rates and has better outcomes interm of preservation of bowel and bladder function whencompared with surgery.35 Other studies reported that IntensityModulated Proton Therapy (IMPT) show greater local controlrates, improved tolerance to treatment and overall survivalrates with a reduced toxicity profile compared withtraditional photon RT.36 Despite the better outcomes ofparticle beam radiation in management of chordomas, theradiation machines used in these treatments are notcommonly available worldwide as they are still very costlyespecially for countries like Thailand.37

Molecular profiles of chordomas have revealed thatchordomas overexpress the platelet-derived growth factorreceptors (PDGFR)B, PDGFRA, and KIT receptors. Thissuggests that there is a role for new molecular-targeting agentssuch as imatinib a tyrosine-kinase inhibitor (TKI).38 Somestudies have shown a good responsiveness to imatinib, a TKIwith specificity for the kinase domain of PDGFR and KITreceptors, in patients with chordoma.39,40 Imatinib has shownthe greatest promise for palliative treatment of advancedchordoma. It can slow down the tumor progression andalleviate patients’ symptoms. Unfortunately, evaluation of its efficacy in current clinical reports is still limited due to smallsample sizes and a relatively long follow-up period. Afatinibis a new drug in recent preclinical studies which is one of theepidermal growth factor receptor (EGFR) inhibitors. Multiplereports in the literature show the activity of different EGFRinhibitors in chordoma cell lines.41 Afatinib might have animmediate therapeutic application for chordoma patients butit is still at the in vivo models stage and needs further investigationin the upcoming phase II study.42

There is as yet no consensus regarding the frequencyand duration of follow-ups for patients with recurrentchordoma. Many experts agree that all patients should receivean magnetic resonance image (MRI) at least every 3-6 monthsfor the first 3 years following treatment. The follow-up periodshould be extended because chordoma can relapse afterseveral years due to its slow growing nature.30

Chordoma is relatively rare. Despite a histology whichmakes it appear to be a benign tumor, chordoma is stillconsidered to be malignant due to its aggressive behavior. Itis usually invasive to the nearby structures and also has a poorprognosis. The treatment of chordomas is challenging becausethey often recur or progress even with the best possible initialtreatment. Recent studies have introduced many treatmentchoices, but there is a paucity of literature on tumor management.Chordoma of the spine is a rare disease and there is verylimited discussion in the literature involving only smallsamples. For these reasons, recurrent chordomas remain extremelydifficult to manage, although management optionscontinue to evolve.

The authors declare no conflicts of interest.