To gain insight into the potential biological relationship between pediatric chordoma and TSC, we compared information on TSC-associated chordomas reported in the literature to data from a systematic population-based assessment of chordomas diagnosed in the US pediatric population up to age 18 years. The results demonstrated that age at diagnosis, primary site of presentation, and possibly outcome differed between chordomas reported in these two populations.
Incidence data in the general US population 2,18
suggest that chordoma may be diagnosed annually in fewer than 1 in 10,000,000 children under age 10 years. Therefore, the development of chordoma by age 16 in all 10 reported patients with TSC is very unusual. More striking, chordoma was diagnosed prior to age 5 in nine of these patients and by age two in seven of them. One possible explanation is that chordoma was diagnosed at a young age in some of them as a consequence of an evaluation for suspected TSC. However, chordoma presented or was diagnosed prior to recognition of TSC in all 9 patients who developed signs or symptoms from this tumor before age 5 suggesting that TSC-associated chordoma may have unusually early onset and/or extremely rapid growth.
In all patients with chordoma, the site of presentation is age dependent.2
Among children with chordoma reported to SEER, over 60% presented with intracranial chordoma, whereas only 9.4% had sacral chordoma. This pattern is in accord with reported clinical series of pediatric chordomas.30–32
In SEER, chordomas in the very young were limited exclusively to the skull base while sacral chordomas were seen only in adolescents. The anatomic location of a chordoma may affect the age at which it is diagnosed, since a slow-growing tumor would be more likely to produce symptoms earlier in the closed intracranial space compared to a tumor originating in the sacrum, regardless of the presence or absence of TSC. However, the site distribution reported thus far for TSC-associated chordoma contrasts sharply with that observed for chordoma in children reported to SEER. In the children with TSC, sacral chordomas accounted for 40% of all tumors, and all four sacral chordomas were diagnosed during the fetal or neonatal period. The early ages at diagnosis of the four TSC-associated sacral chordomas were not necessarily a consequence of increased clinical scrutiny because of suspected TSC: although sacral chordoma was diagnosed within the same time frame as TSC in three of the reported patients, it was diagnosed more than 12 years earlier than TSC in the fourth patient.
Once diagnosed, chordoma appeared to behave differently in TSC patients compared to general pediatric patients. In SEER, median actuarial survival differed by site of presentation. Based on small numbers, patients with sacral chordoma had a median survival of 36 months compared to chordoma at other sites, for which the median had not been reached at study cutoff (> 15 years). Atypical and poorly differentiated chordomas are associated with a poor prognosis in a subset of pediatric patients;32,33
however, we were unable to assess the impact of variant histologies on outcome because these are not recorded in the SEER database. Follow-up was comparatively short for TSC patients with chordoma; however, of the four patients with sacral tumors, two were reportedly alive and free of disease at 8 and 19 years following diagnosis, respectively. Although based on very small numbers, these data suggest that sacral chordoma may have a better clinical outcome in TSC patients than in general pediatric patients.
Our results are based on the assumption that all of the patients reported with TSC and chordoma had both diseases. Five patients (Cases 2, 5, 6, 7 and 8) with two major features20
meet diagnostic criteria for definite TSC; Case 9, with one major feature and one minor feature, fulfills criteria for probable TSC; and Case 4, with one major feature, meets criteria for possible TSC. In addition, the diagnosis of TSC was confirmed in Cases 4 and 5 by the presence in each of a constitutional TSC
mutation, and Case 3 had the same TSC mutation as his affected father. No specific clinical information was provided for Cases 1 and 10: the former was reported to have “classical clinical features (of TSC)”, and the latter patient was said to have epilepsy and a family history of TSC, in particular, a half sibling with a subependymal giant cell astrocytoma. Epilepsy was not the basis for the diagnosis of TSC in Case 10 but its occurrence initiated the evaluation that led to the diagnosis. The fact that clinical features consistent with definite TSC were not reported for every patient is not surprising because most patients were very young at the time of evaluation and may not have yet developed the full clinical phenotype.10
In addition, the case reports varied widely in both the quality and quantity of clinical details and on whether the focus was on TSC or chordoma. However, we believe that further clinical follow-up would have confirmed TSC in all of the patients and that, if mutation analysis had been routinely available and conducted, the probability of detecting TSC1
mutations would have been high.34
Chordoma was reported to be diagnosed on the basis of resection or biopsy of the primary tumor (9 cases) or a metastasis (1 case). No additional information was given for three patients (Cases 1, 3 and 6). Images of tumor histopathology and detailed descriptions of tumor morphology were provided for four patients (Cases 4, 5, 7, 8) and supplemented by immunohistochemistry for three patients (Cases 5, 7, 8). Radiographic characteristics of the tumors were described for five patients (Cases 2, 7, 8, 9, 10) and augmented by magnetic resonance (MR) and/or computed tomographic (CT) images in four (Cases 2, 7, 8, 9).
This study is limited by the small number of reported cases of TSC-associated chordoma, potential biases in ascertainment and reporting of these cases, and the lack of systematically collected data on them. Consequently, we do not know whether the reported cases are representative of TSC-associated chordoma in general. If they are not, then our comparisons with the SEER data on pediatric chordoma and interpretation of the results may not be accurate. In addition, the SEER database is subject to certain well-known constraints,35
although it continues to represent the largest available population-based dataset on chordoma in the US. Despite these substantial limitations, the results suggest that chordoma in the reported children with TSC differs in some important aspects from chordoma in children in the general US population. Germline TSC1/TSC
2 mutations were identified directly in two of the 10 reported patients with TSC-associated chordoma and confirmed posthumously in a third patient. Molecular and immunohistochemical studies of the chordomas from the first two patients with identified mutations demonstrated that one tumor exhibited reduced signal from the wild type TSC1
allele suggestive of LOH as well as absence of staining for hamartin, while the other tumor had clear LOH for the wild-type TSC2
allele and focal very weak staining for tuberin.8
These results support a pathogenetic role for the TSC1/TSC2
genes in these TSC-associated chordomas.
The pathogenetic mechanism(s) underlying the etiology of sporadic chordoma remain unclear. However, reports of TSC-associated chordomas have generated interest in the role of the mTOR signaling pathway in the development of sporadic chordoma. If the mTOR pathway is involved in sporadic chordoma etiology, development of therapeutic inhibitors of molecules associated with the pathway could potentially provide effective treatments for chordoma. Treatment with one mTOR inhibitor has been associated with regression of astrocytomas in patients with TSC.36
Inactivation of TSC1/2
function leads to phosphorylation of mTOR and its downstream effectors, ultimately resulting in initiation of translation, cell growth and proliferation. Mutations in several other components of the mTOR pathway, including Akt, P13K, S6K, LKB1, NF1, PTEN
, or VHL
, can also result in aberrant mTOR activation and are characteristic of several hamartoma syndromes and some cancers.37
In a recent study of 50 ‘typical’ sporadic adult (mostly sacral) chordomas 38
the mTOR pathway was activated in 65% of the tumors. Because TSC2
was phosphorylated in 96% of the studied tumors in the absence of LOH for either TSC1
, mTOR activation may have occurred as a result of post-translational inactivation of TSC1/TSC2
mediated by Akt.
has been shown to be a phosphorylation target of Ras-Erk signaling, with the result that direct phosphorylation of TSC2
leads to inhibition of its tumor-suppressor function.39
No molecular studies of sporadic pediatric chordomas have been reported, so whether activation of the mTOR pathway plays a significant role in the development of these tumors is unknown.
In summary, the reported chordomas in children with TSC were diagnosed at earlier ages and had a different site distribution than sporadic chordomas in the general US pediatric population. Previous work demonstrated somatic inactivation of the TSC genes in the chordomas from two of the TSC patients reported here. These results suggest that chordoma is a rare pediatric manifestation of TSC. Whether chordoma can also be an adult manifestation of TSC is not known. However, a case of chordoma with unusual clinical and anatomical presentation has recently been reported in an adult with TSC.40 Before the relationship between TSC and chordoma can be fully explored, it will be necessary to carefully document the magnitude and clinical spectrum of their joint occurrence. This effort requires that consecutive patients diagnosed with chordoma at any age and site in a defined population be evaluated for TSC, and that the chordomas of those who meet TSC diagnostic criteria or have germline TSC1/TSC2 mutations be examined for TSC1/2 LOH. Meanwhile, future reports of chordoma diagnosed at any age in patients with TSC should provide detailed reporting of the features of both conditions, including the chronology of disease presentation and diagnosis, chordoma immunohistopathology and treatment outcome, and symptoms and signs attributable to TSC. Finally, clinicians who evaluate very young patients with chordoma, especially those with a sacral tumor, should maintain a high index of suspicion for the possibility of undiagnosed TSC.