Chondrosarcomas are indolent but invasive chondroid malignancies that can form in the skull base. Standard management of chondrosarcoma involves surgical resection and adjuvant radiation therapy. This review evaluates evidence from the literature to assess the importance of the surgical approach and extent of resection on outcomes for patients with skull base chondrosarcoma. Also evaluated is the ability of the multiple modalities of radiation therapy, such as conventional fractionated radiotherapy, proton beam, and stereotactic radiosurgery, to control tumor growth. Finally, emerging therapies for the treatment of skull-base chondrosarcoma are discussed.
Key points
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Cranial chondrosarcomas are generally low-grade, indolent malignancies of bone that cause morbidity through compression of neurovascular structures at the skull base.
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The mainstay of treatment for chondrosarcoma is surgical resection followed by adjuvant radiation therapy. Although proton beam radiotherapy is often considered optimal management, multiple radiotherapy modalities demonstrate equivalent efficacy in long-term studies.
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Surgical approaches should be selected based on pattern of tumor growth and attachment, as well as preexisting neurologic deficits.
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Although chemotherapy is not currently part of the standard treatment regimen for chondrosarcoma, emerging molecular-targeted therapies may contribute to tumor control in the future.
Introduction
Chondrosarcoma is the second most common primary malignancy of bone, arising from cells of chondroid (cartilage) origin throughout the axial and appendicular skeleton. Only 1% of chondrosarcomas arise in the skull base, and account for 6% of all skull-base tumors. The vast majority of cranial tumors are low to intermediate grade with indolent growth and low metastatic potential. However, their intimate association with critical neural and vascular structures at the skull base often results in significant morbidity from tumor growth and surgical intervention. The mainstay of therapy for chondrosarcoma is surgical resection, with fractionated radiation therapy used to limit recurrence. Recently, radiosurgery has been investigated as an alternative to fractionated radiotherapy. There has been little role for chemotherapy in the treatment of this disease.
This review examines the published literature on the management of cranial chondrosarcoma, including the importance of the extent of microsurgical resection and the multiple modalities of adjuvant radiation including radiosurgery, proton beam, and heavy-particle radiotherapy. The goal is to provide an evidence-based guideline for the management of this rare and complicated disease. In addition, laboratory evidence is presented for new molecular targets to improve emerging chemotherapies for chondrosarcoma.
Introduction
Chondrosarcoma is the second most common primary malignancy of bone, arising from cells of chondroid (cartilage) origin throughout the axial and appendicular skeleton. Only 1% of chondrosarcomas arise in the skull base, and account for 6% of all skull-base tumors. The vast majority of cranial tumors are low to intermediate grade with indolent growth and low metastatic potential. However, their intimate association with critical neural and vascular structures at the skull base often results in significant morbidity from tumor growth and surgical intervention. The mainstay of therapy for chondrosarcoma is surgical resection, with fractionated radiation therapy used to limit recurrence. Recently, radiosurgery has been investigated as an alternative to fractionated radiotherapy. There has been little role for chemotherapy in the treatment of this disease.
This review examines the published literature on the management of cranial chondrosarcoma, including the importance of the extent of microsurgical resection and the multiple modalities of adjuvant radiation including radiosurgery, proton beam, and heavy-particle radiotherapy. The goal is to provide an evidence-based guideline for the management of this rare and complicated disease. In addition, laboratory evidence is presented for new molecular targets to improve emerging chemotherapies for chondrosarcoma.
Pathology
Cranial chondrosarcoma occurs primarily at the base of the skull, arising from rests of chondrocytes within the synchondroses of the basilar skull bones. Tumors are found most often in the paraclival region arising from sphenopetrosal, petro-occipital, or spheno-occipital synchondroses. The vast majority of lesions involve the bone of the clivus, and extend anteriorly into the parasellar sinuses or middle cranial fossa (30%–50%), or posteriorly into the posterior fossa (50%). Although invasion through the dura is uncommon, compression of the brainstem or temporal lobe is frequent at presentation ( Fig. 1 ). Cranial chondrosarcoma occurs preferentially at the skull base, owing to differences in bone development between the cranial vault and the basilar structures. The cranial vault grows primarily by intramembranous ossification, whereas the basilar skull bones develop by endochondral ossification and retain rests of chondrocytes into maturity, which can undergo malignant degeneration. Most chondrosarcomas develop sporadically, although tumor formation has been associated with diseases of endochondroma formation including Ollier disease and Maffucci syndrome.
Chondrosarcoma manifests grossly as a destructive, mineralized mass that invades bone and extends into soft tissues. Lesions typically grow in bone with an infiltrative pattern, replacing normal marrow elements and spreading through Haversian canals. Eventually lesions break through the cortex and invade surrounding soft tissue. Histopathologically, chondrosarcomas can be of the conventional, mesenchymal, clear-cell, or dedifferentiated type. Almost all skull-base tumors are the conventional type, with rare (<10%) mesenchymal lesions reported. The clear cell and dedifferentiated types do not occur in the axial skeleton. Conventional chondrosarcoma can be composed of hyaline or myxoid cartilage, or a combination of the two ( Fig. 2 ). Conventional lesions are graded according to the degree of cellularity, cytologic atypia, and mitotic activity on a 3- or 4-tiered scale, with the lowest grade representing well-differentiated tumors. In the 2 largest case series of skull-base chondrosarcoma reported in the literature, 50% of the lesions were low grade (grade 1) and nearly 90% were low to intermediate grade (grade 1–2). High-grade, poorly differentiated lesions of the conventional subtype are rare in all anatomic locations, and identification of aggressively invasive, poorly differentiated cartilage should raise the possibility of chondroblastic osteosarcoma.
Chondrosarcomas, especially low-grade tumors, have relatively indolent growth compared with other sarcomas. Nonetheless, they are highly invasive and have the potential for distant metastasis. Approximately 7% of patients have distant metastasis, which is most commonly seen with high-grade conventional tumors and the mesenchymal subtype.
Clinical presentation
Data from the national cancer database indicates that the median age at presentation for cranial chondrosarcoma is 51 years, with a slight male predominance (55% of cases). Most cases (85%) occur in non-Hispanic white patients. As indicated previously, most cases demonstrate a conventional histologic subtype with low-grade pathology. Fewer than 10% of cases are of the mesenchymal subtype, and these patients tend to be younger, with greater than 60% of cases occurring in patients younger than 30 years.
Because of the location of most tumors in the skull base, along the spheno-petro-clival junction, the majority of patients present with symptoms of cranial nerve compression. In a series of 33 patients with cranial chondrosarcoma managed at the University of California, San Francisco, the most common presenting symptoms were headache and diplopia, with nearly 50% of patients presenting with palsy of the sixth cranial nerve. A similar presentation was reported by groups from the Barrow Neurological Institute and the International Neuroscience Institute in Hannover, whose series contained mostly clivus-invading tumors causing sixth-nerve dysfunction from compression within the Dorello canal. By contrast, the group from the House Clinic reported on 8 patients with a predominance of petrous apex tumors extending into the cerebellopontine angle who all presented with dysfunction of the lower cranial nerve. The presence of particular cranial-nerve deficits at presentation can be an important factor in the selection of surgical approach, especially with regard to function of cranial nerve VIII and the feasibility of a transpetrosal approach.
The differential diagnosis for skull-base lesions in the typical location of a cranial chondrosarcoma includes chordoma, other primary bone tumors, skull-base metastases, meningiomas, schwannomas of the lower cranial nerve, neuroblastoma, and lymphoma. Although any of these expansile lesions may cause bony remodeling, erosive destruction of the petrous apex or clivus is not generally associated with lesions other than chondrosarcoma, chordoma, or metastases. Therefore, in addition to magnetic resonance imaging, computed tomography and plain radiographs may be useful in determining the diagnosis.
Management
Surgical Resection
The current standard for initial treatment of cranial chondrosarcoma is surgical resection to obtain a definitive tissue diagnosis and maximally cytoreduce the tumor. Selection of the approach to the skull base is principally determined by the primary direction of tumor growth and the involved cranial nerves. Tumors involving the petrous apex and upper third of the clivus with extension anteriorly into the Meckel cave or the cavernous sinus are often addressed through a frontotemporal orbitozygomatic approach, or a pure middle-fossa craniotomy with subtemporal dissection. By contrast, posteriorly and inferiorly directed tumors extending below the internal acoustic canal are best treated through a retrosigmoid or transpetrosal approach. Large tumors may require a combined petrosal/middle-fossa approach or a staged procedure. Among a group of combined modern surgical case series for skull-base chondrosarcoma, approximately a third of tumors were resected via an anterior approach, a third via a posterolateral approach, and a third via alternative approaches including transfacial and transsphenoidal approaches. Endoscopic transnasal approaches have also been reported with success for specific tumors.
Preoperative cranial-nerve deficits are common in cranial chondrosarcoma patients, with the most common presenting symptom being diplopia secondary to dysfunction of cranial nerve VI. Given the invasive nature of chondrosarcoma and the difficult location of most tumors at the skull base, improvements in cranial nerve deficits after surgery are uncommon, and the potential for causing new deficits with surgery is significant. In their series of 18 patients, Samii and colleagues found that 16 of 18 (89%) patients had at least a partial cranial neuropathy at presentation. After surgical resection 25% had new cranial nerve deficits, whereas 55% had no improvement in their preoperative symptoms. Similarly, Sekhar and colleagues reported 41% new cranial neuropathies in their series of 22 chondrosarcoma patients. In addition to cranial neuropathies, modern surgical series also report an approximately 10% to 15% rate of vascular injury, 10% rate of cerebrospinal fluid leak, and up to 5% perioperative mortality. Given the relatively high morbidity of such procedures, there is some controversy in the literature regarding the goals of operations. Some investigators have argued that the goal for initial intervention should be aggressive gross-total resection, as this offers the possibility for a surgical cure. The groups that advocate this approach report a complete resection achieved in 50% to 60% of patients. By contrast, others have argued for an approach using maximal safe cytoreduction followed by radiotherapy to control residual tumor growth. In general, 5-year tumor-recurrence rates and overall survival were 70% to 80% and 80% to 90%, respectively, regardless of the approach used. There is no direct evidence to suggest that extent of resection at the initial operation offers any recurrence or survival benefit when adjuvant radiation is given.
The authors previously performed a systemic analysis of the published literature on cranial chondrosarcoma, disaggregating the data from individual case series to statistically evaluate predictors of tumor recurrence and overall survival. The cumulative data from all published series of cranial chondrosarcoma demonstrates a recurrence-free survival of 78% at 5 years and an overall survival of 88% at 5 years. The greatest predictor of outcome was tumor histology, with mesenchymal-type tumors showing nearly 5-fold greater 5-year mortality ( Fig. 3 A). Within conventional type tumors, tumor grade was associated with worsening survival ( Fig. 3 B). However, mesenchymal and high-grade conventional tumors were rare, representing fewer than 11% of all cases. For the majority of patients, outcome was significantly affected by the use of adjuvant radiation. The authors’ analysis found that 5-year mortality was decreased from 25% to 9% with the addition of any form of radiation ( Fig. 3 C). A recent case series of 6 patients with cranial chondrosarcoma treated with surgical resection followed by fractionated radiotherapy found 100% tumor control at 5 years irrespective of the residual tumor volume after resection, which ranged from 0 to 28.7 cm 3 . Although this is a small series it supports the trend seen in the surgical data, which indicate that survival outcomes are approximately the same regardless of the extent of surgical resection. A robust analysis of the effect of extent of resection on a group of chondrosarcoma patients with equivalent adjuvant therapy has not been performed, leaving this issue open for debate.
