Background
Chordoma is a rare, locally invasive bone tumor of notochordal origin with an incidence of 0.1 to 0.8/1,000,000 [
1‐
3]. It is 40 % less likely in females compared to males [
2,
4]. The tumor can present at the base of the skull, in the vertebral column, or in the sacral region, but there is controversy over the relative incidence at these sites [
2,
5]. Although chordomas are typically a tumor of the aged, presentation in younger individuals tends to occur at the skull base [
2,
4,
6]. In addition, female gender is associated with greater likelihood of presentation in the skull base [
2,
4]. The overall median survival after chordoma diagnosis is approximately 6 years, but it is higher for tumors with chondroid histology and lower for those with dedifferentiated histology compared to the conventional variety [
2,
7].
Skull base chordomas are typically surgically resected and proton beam therapy is often used to treat residual tumor [
8,
9]. We report the first case, to the best of our knowledge, of a skull base chordoma that dedifferentiated after proton beam therapy. A timeline of the case is shown in Table
1.
Table 1
Timeline of the patient’s clinical course
16 Jun 2012 | Initial presentation with headaches and emesis prompts magnetic resonance imaging that shows a large heterogeneous skull base mass suspicious for chordoma. |
2 Jul 2012 | Endonasal surgical resection. Surgical pathology confirms chordoma diagnosis. |
2 Nov – 29 Nov 2012 | Fractionated proton and photon beam therapy: 77.4 Gy total, 59.4 Gy (cobalt gray equivalent) in 33 fractions with protons and 18 Gy in 10 fractions with photons. |
18 Jun – 11 Dec 2013 | Interval decrease in tumor size visualized at scheduled magnetic resonance imagings. |
3 Jan 2015 | Visual disturbances prompt magnetic resonance imaging, which shows an enhancing mass in the resection site suspicious for recurrence with dedifferentiation. |
21 Jan 2015 | Retrosigmoid craniotomy. Surgical pathology shows complete dedifferentiation. |
29 Mar 2015 | Begins ifosfamide and etoposide alternating every 2 weeks with vincristine, doxorubicin, and cyclophosphamide. |
23 Apr 2015 – 25 Mar 2016 | Interval decrease in tumor size visualized at scheduled magnetic resonance imagings. Continues ifosfamide and etoposide alternating every 2 weeks with vincristine, doxorubicin, and cyclophosphamide. |
26 Apr 2016 | Last of 17 cycles of ifosfamide and etoposide alternating with vincristine, doxorubicin, and cyclophosphamide. Begins maintenance capecitabine. |
Discussion
Less than 5 % of chordoma diagnoses occur in children under 10 years of age [
2]. Among childhood cases, Borba and colleagues found a distinct difference in presentation, tumor morphology, and prognosis between cases occurring in children under and over age 5 [
10]. Children under age 5 frequently have long tract deficits [
11,
12] and intracranial hypertension, and the tumor is often of an atypical morphology, which has a poor prognosis [
10]. Children over age 5 most frequently present with double vision [
13‐
17] and headaches [
13,
18,
19], have typical tumor morphology, and, thus, survive for longer [
10]. Our patient, an 8-year-old girl presenting with headaches and nausea, was found to have a typical clival chordoma, which initially fit the expected pattern of disease presentation. The histology and imaging appearance of her tumor, though, changed with recurrence 2.5 years after the initial surgical resection and radiation therapy.
Chordomas show dual epithelial-mesenchymal differentiation as they arise from embryonic remnants of the notochord [
20]. Although the molecular pathogenesis of chordoma is not fully known, brachyury has been shown to be both a regulator of notochordal differentiation and a chordoma marker. Cytogenetic studies have shown that mutations on multiple chromosomes are associated with chordoma [
21]. Conventional chordomas feature large polygonal cells with abundant eosinophilic to amphophilic cytoplasm, variable nuclei, and occasional vacuoles (physaliferous cells) arranged in cords and sheets in a myxoid stroma [
22,
23]. Chondroid chordomas have regions where the stroma resembles hyaline cartilage and neoplastic, sometimes physaliferous, cells grow in lacunae [
22,
23]. Finally, dedifferentiated chordomas have regions of or have become entirely composed of malignant sarcomatous cells [
22,
24]. Previous reports have shown possible loss of EMA and cytokeratin [
24,
25], but our case is the first to report absence of brachyury in the dedifferentiated tumor. In addition, dedifferentiation was faster than in earlier reports of completely dedifferentiated chordoma occurring after conventional radiotherapy [
26,
27].
T1-weighted MRI shows chordomas as having predominantly intermediate to dark signal [
28]. They are typically bright on T2-weighted MRI, but dedifferentiated chordomas are not [
29]. Diffusion-weighted MRI will show diffusion restriction, but this may be difficult to interpret in skull base tumors due to artifact at the skull base [
30]. Contrast enhancement is variable [
31]. Further advancements in molecular imaging may allow for definitive diagnosis without the need for biopsy. Much as immunohistochemistry is used to identify proteins in biopsies, radiolabeled molecular probes and targeted MRI contrasts may be used in the future to identify unique proteins in neoplasms [
32]. Skull base chordomas most often involve the upper half of the clivus and often extend to the lower half of the clivus, posterior clinoid process, cavernous sinus, and occipital condyle [
30]. Our patient’s tumor showed typical MRI presentation when she first presented to us. However, the resection site recurrence had intermediate to dark signal on T2-weighted images.
Most recent research indicates the overall prognosis for younger patients is better than for adult patients with chordoma, although there have been contradictory findings [
3,
4,
23,
30]. Surgical margins are the most important prognostic indicator for patients without dedifferentiated chordoma, and gross resection or debulking is recommended for patients without contraindications [
8]. However, dedifferentiated chordomas are less responsive to surgery and carry a worse prognosis [
8,
33]. Residual tumor in the resection cavity responds best to high doses of radiation, which creates a difficulty when treating clival tumors because the adjacent structures are critical and radiosensitive [
8]. Proton beam therapy is used to deliver high doses of radiation (70 to 80 GyE) with less damage to non-neoplastic tissue than conventional photon radiotherapy due to its sharp Bragg peak [
9,
34]. However, side effects such as radiation necrosis of the optic nerve and temporal lobe, epilepsy, inhibition of the hypothalamic–pituitary axis, and other endocrinopathies have been reported [
8,
34,
35]. Hara and colleagues reported the only case of a sarcomatoid transformation after proton beam therapy, which occurred 3 years after the initial treatment and 1 year after a second course of proton beam therapy [
36]. It is important to note that some authors distinguish between sarcomatoid chordoma and dedifferentiated chordoma in that the first retains immunoreactivity for cytokeratin, whereas the latter does not [
24,
37].
Acknowledgements
The authors thank the physicians, nurses, and pharmacists who cared for the patient, and the patient’s family for allowing this case report.