Chordoma Occurs in Young Children With Tuberous Sclerosis

Abstract

Chordomas are rare bony neoplasms usually unassociated with a familial tumor predisposition syndrome. The peak incidence of this midline axial skeletal tumor is in adulthood but when very young children are affected, consideration should be given to occurrence within the tuberous sclerosis (TS) complex, especially when presenting in neonates <3 months of age. To call attention to this association, we present a brachyury-immunopositive chordoma occurring in the skull base of a 2-month-old male infant who was later realized to have metastases to the subcutaneous tissues and lungs, as well as rhabdomyoma of the heart and renal cysts/angiomyolipomas, that is, characteristic features of the TS complex. We review the limited literature on this topic.

INTRODUCTION

Chordomas are bony neoplasms that typically arise in the midline axial skeleton from the spheno-occipital skull base to the sacrococcygeal region. Unlike the more balanced anatomical distribution throughout the skull and spinal column in adult populations, pediatric chordomas arise as intracranial lesions in more than 60% of cases (1). They are derived from remnants of the embryonic notochord and driven by perturbations in brachyury, a transcription factor crucial in regulating notochord formation (2).

Chordomas are rare, with a Surveillance, Epidemiology, and End Results (SEER) age-adjusted incidence rate of 0.08 per 100,000. Of these, <5% of chordomas are diagnosed within the pediatric population (1). Association with tuberous sclerosis complex (TSC) has been previously described and correlates with an earlier patient age at diagnosis (3). Metastatic disease is rare, but is reported more commonly in children, particularly under the age of 5 years (4, 5). While isolated congenital sacral or clivus chordoma has been previously reported in the literature (6–10), widely metastatic congenital chordoma in an infant with TSC has not. We review the limited literature on the rare association of chordoma with TSC.

CASE PRESENTATION

A previously healthy 2-month-old male infant presented with an enlarged head size and 2 days of decreased oral intake. On presentation, his parents also called attention to his firm blue-colored skin nodules on his scalp, trunk, and lower extremities that had been present at birth and had grown in size and number over time. Further questioning of the parents and examination revealed seizures and developmental delay.

Magnetic resonance imaging (MRI) showed a large, extraaxial, heterogenous skull base mass on T1-weighted imaging, with severe distortion of the brainstem and resultant severe obstructive hydrocephalus (Fig. 1A). Axial T2-weighted images demonstrated a cystic portion within the hypointense mass along its left aspect, with fluid–fluid level (Fig. 1B, arrow); by susceptibility weighted imaging, this reflected blood products (Fig. 1C).

FIGURE 1.

(A) Magnetic resonance imaging (MRI), sagittal T1-weighted, shows the large, extraaxial, heterogenous skull base mass, with marked distortion of the brainstem and resultant severe obstructive hydrocephalus. (B) MRI, axial T2-weighted, demonstrates a cystic portion within the hypointense mass along its left aspect, with fluid–fluid level (arrow). (C) MRI, with susceptibility weighted imaging, implies that the hypointense signal reflected blood products. (D) MRI imaging of the body demonstrated multifocal, bilateral, hemorrhagic renal cysts. (E, F) MRI, T2-weighted, showed hyperintense lesions in the liver, spleen, paraspinal (E, arrow) and other (E, arrowhead) musculature, as well as subcutaneous tissues (F, arrow).

Additional body MRI scans demonstrated multifocal, bilateral, hemorrhagic renal cysts (Fig. 1D) with T2 hyperintense lesions in the liver, spleen, paraspinal muscles and subcutaneous tissues (Fig. 1E, F). Bilateral pulmonary nodules up to 8 mm in size were also noted. A screening echocardiogram revealed multiple rhabdomyomas in the right cardiac ventricle. Careful dermatological examination disclosed no ash leaf macules or other skin abnormalities beyond the skin nodules. Ophthalmology exam was negative. General exam revealed hypertension, requiring pharmacologic intervention with antihypertensives.

Biopsies of a chest wall skin nodule and the clival tumor were obtained. Pathological examination of the chest wall mass revealed a lobular chordoma composed of chains and cords of bubbly physaliphorous cells embedded within an abundant mucinous matrix (Fig. 2A, B). No atypical or dedifferentiated features were present and mitotic activity was not observed, even in the metastatic chest wall mass (Fig. 2A, B). Cells manifested the typical cytoplasmic immunostaining for epithelial membrane antigen (EMA) (Dako, Carpinteria, CA, 1/200 dilution, with antigen retrieval) (Fig. 2C), S100 protein (Dako, 1/1000 dilution, no retrieval), AE1/AE3 (Cell Marque, Rocklin, CA, 1/100 dilution, with antigen retrieval), strong nuclear brachyury expression (PhenoPath, Seattle, WA) (Fig. 2D), and retention of nuclear INI-1 expression (BD Biosciences, San Jose, CA, 1/250 dilution, with antigen retrieval) (Fig. 2E). The clival mass biopsy was histologically identical (Fig. 2F).

FIGURE 2.

(A) Biopsy of the chest wall skin nodule showed a well-demarcated metastatic subcutaneous tumor with characteristic lobularity and abundant grayish-blue extracellular matrix. Hematoxylin and eosin (H&E), 40×. (B) Higher power magnification of the metastatic chest wall skin nodule discloses the typical histological features of chordoma, including bubbly physaliphorous cells and lobularity. H&E, 200×. (C) Cytoplasmic immunoreactivity for epithelial membrane antigen (EMA) in the skin nodule (along with immunoreactivity for S100 protein and AE1/AE3 keratins [not shown]); the cytoplasmic vacuoles are further negatively outlined by the EMA IHC. Immunostaining for EMA with light hematoxylin counterstain, 400×. (D) Strong diffuse nuclear immunoreactivity in the skin nodule for brachyury highlights the lobularity of the tumor and further cements the diagnosis of metastatic chordoma. Immunostaining for brachyury with light hematoxylin counterstain, 200×. (E) Retention of nuclear immunostaining for INI1 protein both within tumor nuclei and endothelial cell nuclei of blood vessels within the tumor. Immunostaining for INI1 protein with light hematoxylin counterstain, 400×. (F) The clival mass showed identical histological features as that of the chest wall skin metastatic nodule, that is, classic chordoma with numerous vacuolated physaliphorous cells. H&E, 600×.

Next generation sequencing (NGS) revealed biallelic loss of TSC-1 gene in the tumor cells; however, germline TSC1 and TSC2 sequencing and deletion/duplication analyses found no abnormal variants. Chromosomal microarray was also normal with no significant gains or losses, and cytogenetic analysis was normal showing 46, XY karyotype. Extensive family history was reviewed and found to be negative for significant childhood illnesses, seizure disorders, renal dysfunction, and brain or other tumors in family members. Given the constellation of typical TS findings in the patient, the Clinical Genetics team felt that the best explanation was that the patient had mosaicism for TS or that he had a smaller germline mutation that could not be identified that led to TSC1 loss in the tumor.

DISCUSSION

Chordoma remains a rare and poorly described disease entity within pediatric patients but there is growing evidence for correlation with TSC in this population. In the patient presented here, early clinical characteristics of TSC, including cardiac rhabdomyoma and polycystic kidneys, were associated with TSC1 loss within evaluated tumor cells. Systemic genetic testing was normal, creating 2 possibilities. First, it is possible we did not detect the known pathogenic genetic variant causing TSC, which occurs in 10%–25% of patients who fit the clinical criteria (11). A second possibility is that this patient has somatic mosaicism. Normal conventional testing results do not exclude TSC and patients may be diagnosed by clinical criteria alone. Our patient presents with one major feature (cardiac rhabdomyoma) and 1 minor feature (multiple renal cysts), resulting in a “possible” diagnosis of TSC. This patient also presented with additional clinical features associated with TSC including seizures and developmental delay. A number of the other diagnostic clinical features of TSC tend to arise over time and are not necessarily evident at birth. Indeed, in our patient at age 4 months, he is below the age at which many described TSC criteria emerge (11). Based on the strong clinical findings and identification of TSC1 loss in the tumor, recommendations by Clinical Genetic services included considering this patient as having TSC and providing appropriate interventions.

Although not widely known, chordomas have previously been reported in children diagnosed with TSC, an autosomal dominant familial tumor predisposition syndrome resulting in hamartomas in multiple tissues. One retrospective review that compared the SEER database of the National Cancer Institute (NCI) to a literature review of children with TSC and chordoma made the observation that children with TSC appear to be diagnosed with chordomas at earlier ages than peers without TSC, and they were more likely to present with a sacral location rather than skull base chordomas (3). Those with TSC and sacral chordomas may have longer median survival than peers without TSC. Conclusions from this study are, however, limited by small sample size (10 patients younger than age 18 were reported in the literature to have both chordoma and TSC, compared with 65 patients with histologically confirmed chordoma in the SEER database). This reflects the overall rarity of chordoma in pediatric patients, which has been reported in <1 in 10,000,000 (1).

In addition to the strong clinical suspicion for TSC, our patient had demographic features paralleling those of chordomas reported in previous TSC patients (Table). A comparison of our 2-month-old patient (Case no. 1) to patients with TSC-associated chordoma in the literature shows similarities including an early age of presentation, with the median age at diagnosis with TSC-associated cases at 6.2 months of age (3). Indeed, when including our case, 7 of 13 published examples have been either prenatal or neonatal diagnoses (i.e. in children <3 months of age) and 2 more occurred children <2 years (in a 9- and 20-month-old) (Table). Additionally, the majority of reported TSC-associated chordoma patients carry a clinical TSC diagnosis, as does our patient (Table), rather than proven genetic mutation. Although the numbers of reported cases are quite small (n = 13), collectively the reports suggest that chordoma is truly a feature of predominantly very young patients with TSC, may even be a congenital diagnosis, and that the clinical outcome for TSC patients with chordoma is relatively favorable, with some survivors showing no evidence of disease 4–18 years after diagnosis (Table). On our review of these literature cases, no other single TSC-associated finding was strongly, or exclusively, coassociated with chordoma occurrence in these cases, that is, the patients manifested a wide range of typical TSC features.

TABLE.

Reported Cases of Chordoma Associated With Tuberous Sclerosis

Case No.	Age at Diagnosis	Sex	Primary Site of Disease	Metastases	TSC Diagnosis	Outcome	Reference
1	2 mo.	M	Clivus	Yes	Clinical	Insufficient followup time	(present case)
2	Neonate	M	Sacrum	No	Clinical	NED at 19 yrs.	(6, 10)
3	4.5 yrs.	F	Skull base	No	Clinical	NR	(31)
4	4 yrs.	M	Clivus	No	TSC1 nonsense mutation, G2045T, exon 15	Dead at 2 yrs.	(32)
5	Prenatal	F	Sacrum	No	TSC2 nonsense mutation, Q1010X, exon 26	NA	(9)
6	5 days	F	Sacrum	No	SC1 9 bp in-frame deletion, 402_410delCTGACCAC, exon 4	NED at 8 yrs	(9)
7	3 days	M	Sacrum	No	Clinical	NED at 26 mo.	(8)
8	20 mo.	M	Clivus	Yes	Clinical	NED at 5 yrs.	(12)
9	15 wks.	M	Skull base	Yes	Clinical	NR	(13)
10	16 yrs.	F	Spine	No	Clinical	NED at 1 yr.	(33)
11	9 mo.	M	Clivus	No	Clinical	NED at 5 yrs.	(34)
12	38 yrs.	M	Lateral medullary cistern	No	Clinical	NR	(35)
13	Neonatal	M	Sacrum	No	TSC2	NED at 4 yrs	(7)

F, female; M, male; NA, not applicable; neg, negative; NED, no evidence of disease; NR, not reported; pos, positive; TSC, tuberous sclerosis complex; mo., months; yrs, years.

Even less common that clival or sacral chordoma in TSC patients is metastatic disease. Our patient presented at birth with firm blue-colored skin nodules, which were later identified as metastatic chordoma lesions, concordant with the diagnosis of congenital metastatic chordoma in an infant with TSC. Metastatic chordomas in young TSC patients have been previously reported, including in a patient diagnosed at 20 months of age who had asymptomatic skin nodules initially noted at 6 months of age (12). A second young infant without TSC but with a diagnosis of metastatic chordoma at 15 weeks of age, including pulmonary involvement and C6 bony metastatic disease, has been reported (13).

Old classification systems separated chordoma into 3 types, chordoma, chondroid chordoma, and dedifferentiated chordoma. Today, however, 2 types are recognized: chordoma and dedifferentiated chordoma. Dedifferentiated chordoma is a biphasic tumor, comprising the features of chordoma not otherwise specified, juxtaposed with a high-grade undifferentiated spindle cell tumor or osteosarcoma. In a review of 79 pediatric cases of chordoma, Borba et al reported that increased mortality from disease was strongly associated with dedifferentiated histology (4). More recent series have shown similar findings, with mortality rates of 14%–38% reported for classical (or chondroid) subtypes in comparison to 66%–100% for those with dedifferentiated features (4, 14–16). Our patient showed no dedifferentiated features histologically in either the metastatic skin lesion or the clival lesion.

Loss of SMARCB1/INI1 expression, the genetic hallmark of malignant rhabdoid renal tumors and atypical teratoid/rhabdoid tumors, has been described in poorly differentiated chordomas and may in part account for this adverse prognosis (17, 18). The INI1 protein status was evaluated in our case and was shown to be retained in nuclei, indicating no mutation of SMARCB1/INI1. Paralleling the fact that chordomas are derived from remnants of the embryonic notochord and driven by perturbations in brachyury, which encodes a transcription factor crucial in regulating notochord formation (2), our case showed strong diffuse nuclear brachyry protein expression by immunostaining, further verifying the diagnosis of chordoma.

TSC1 and TSC2 are tumor suppressor genes coding for hamartin and tuberin in the mTOR (mechanistic target of rapamycin) pathway, a complex regulatory system involved with entry into the G1 phase of the cell cycle. TSC inactivation ultimately releases a negative control on mTOR, leading to phosphorylation of S6 ribosomal protein (RPS6) and eukaryotic translation initiation factor 4E (eIF-4E), thought to result in activation of the abnormal growth of multiple tissues including facial angiofibroma, cardiac rhabdomyoma, subependymal nodules, and subependymal giant cell astrocytomas, which are clinical characteristics of patients with TSC (19).

Given the central role of mTOR in TSC pathogenesis, mTOR inhibitors have emerged as an approach to therapy for several tumor types in TSC. The EXIST-1 trial examined everolimus for the treatment of subependymal giant cell tumors in the setting of TSC, and found >50% reduction in tumor size in a significant proportion of patients compared to placebo (20). mTOR inhibition has been shown to be a useful strategy for those with TSC related to refractory epilepsy (21), renal angiomyolipomas (22), pulmonary lymphangioleiomyomatosis (23), and facial angiofibromas (24). Although there are no trials to specifically examine mTOR inhibition for chordoma in TSC to date, molecular data suggests that mTOR inhibition may be useful to treat up to 65% of sporadic chordomas (19).

The mainstay of chordoma therapy has been aggressive local control with maximal surgical resection followed by adjuvant radiotherapy (16, 25). While this approach may not be feasible in the case of widely metastatic disease, such as in our patient, evidence for systemic chemotherapy in the management of advanced chordoma is limited. Literature surrounding cytotoxic chemotherapy consists largely of anecdotal reports and small case series of varied treatment regimens, including alkylating agents, anthracyclines, and platinum-based compounds (26, 27).

Targeted therapies have become the focus of current research, with agents inhibiting epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), mTOR, and vascular endothelial growth factor (VEGF) pathways having demonstrated some evidence of disease activity (28). PDGFR inhibition with the tyrosine-kinase inhibitor imatinib has shown promise of clinical benefit in one prospective phase II study (29); and an adult phase II study of imatinib plus everolimus is currently underway following retrospective data suggesting synergy with mTOR inhibition (30). Identification of TSC1 loss in our patient’s tumor suggests use of mTOR inhibition with everolimus in addition to cytotoxic chemotherapy is a potential therapeutic option. Thus, we elected to place our patient on a platinum-based therapy with the addition of everolimus; the interval of treatment remains too short to assess efficacy.