Primary Skull Base Chondrosarcomas: Comparison
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Primary skull base chondrosarcomas (SBCs) may carry significant tumor-burden by causing severe cranial nerve neuropathies. Current treatment strategies mainly focus on surgical resection and radiotherapy protocols, with a wide range of findings in terms of efficacy and safety. 

  • chondrosarcoma
  • endoscopy
  • radiation oncology

1. Introduction

Chondrosarcomas comprise a heterogeneous group of malignant tumors originating from chondroid cells throughout the appendicular and axial skeleton. The skull base is involved in approximately 1% of cases, with skull base chondrosarcomas (SBCs) accounting for 0.15% of all intracranial neoplasms [1,2][1][2]. Despite the proven association with Ollier’s and Maffucci’s diseases, SBCs mostly arise de novo [3]. Their pathogenesis appears to be linked to the endochondral ossification of the skull base synchondroses, as most tumors involve the clivus and the temporo-occipital junction [4,5][4][5]. Amongst the histopathological subtypes, conventional chondrosarcomas represent the vast majority and are classified into WHO grades I (well-differentiated), II (intermediate), and III (poorly differentiated) [6,7][6][7].
While low-grade SBCs may be indolent and slow-growing, poorly differentiated neoplasms are highly invasive, destructive, and may metastasize. Symptoms derive from the direct compression of cranial nerves and neurovascular structures at the base of the skull, with headache and diplopia being the most frequent [5,8][5][8]. Computer tomography (CT) scans can evaluate bone invasion and destruction, but magnetic resonance imaging (MRI) provides better delineation of soft tissue involvement in skull base chondromas [8,9,10][8][9][10]. The main goals of surgery are tissue diagnosis and maximal safe resection, in order to prevent neurological deterioration, optimize conditions for dose-escalated adjuvant radiotherapy, and improve survival. Gross total resection is safely feasible in some cases, but has higher risks of postoperative neuropathies and vascular injuries [11,12][11][12]. Thus, adjuvant radiotherapy is often administered to treat any residual disease following safe maximal cytoreduction, further enhancing local tumor control and survival [11,13][11][13]. Novel proton-based and carbon ion-based radiotherapy modalities have also been studied to focus high dose radiation beams to selected tumor targets, reducing radiation-induced toxicities to the normal brain tissue [14,15][14][15].

2. Primary Skull Base Chondrosarcomas

Primary SBCs are uncommon but challenging entities with a major impact on patients’ quality of life. Current management strategies are aimed at relieving symptoms, tumor control, and protecting functional status, but related complications need to be considered. 

Primary SBCs’ incidence peaked between the fourth and sixth decades of life, similarly to previous reports on spinal and laryngeal chondrosarcomas from national cancer databases and systematic reviews [49,50,51][16][17][18]. However, while spinal chondrosarcomas mostly affect men, primary SBCs showed no gender predilection, probably suggesting underlying molecular differences that deserve further evaluation [50,51][17][18]. Chondrosarcomas are deemed to originate from chondroid cells and are grouped in different histological subtypes based on cellular appearance [7]. Regardless of the anatomical location, conventional chondrosarcomas represent the vast majority, mostly of low/intermediate grade with slow growth patterns; the other less common subtypes, such as mesenchymal, identify high-grade aggressive variants [49,51,52,53][16][18][19][20]. Similarly, most tumors in our review were conventional SBCs (84.5%) of low (59.9%) or intermediate grade (37.6%), while mesenchymal SBCs showed the worst prognoses [38,39][21][22]. Chondrosarcomas may also derive from the de-differentiation of primary enchondromas, which may occur more frequently in patients with congenital systemic enchondromatosis [54,55][23][24]. Indeed, some patients with primary SBCs had underlying Ollier’s (0.9%) and Maffucci’s (0.2%) syndromes, in line with the current literature on axial chondrosarcomas [51,52][18][19]. In these cases, management strategies are complex and multi-disciplinary treatment approaches are recommended [55][24].

Most patients with primary SBCs experienced mild and slowly progressing symptoms for a median duration of 16 months before requesting medical assistance. Similar findings have been reported in patients with spinal and laryngeal chondrosarcomas, likely suggesting that these entities mostly carry indolent clinical courses following their slow growth patterns [49,50][16][17]. Still, the acute onset of symptoms in some patients may suggest that some primary SBCs may remain asymptomatic until the occurrence of severe neurologic compromise, while other SBCs, especially high grade or non-conventional, may show rapid tumor progression and neurological impairments [23,39,48][25][22][26]. Symptoms of primary SBCs reflect their location within the skull base and their proximity to critical neurovascular structures [17,36][27][28]. Most primary SBCs occurred in the middle fossa, mainly involving the petrous bone (37.8%), the clivus (23.5%), and/or the petroclival synchondrosis (20.2%), and also compressing the brainstem (49.7%) and/or invading the cavernous sinus (42.4%). Hence, tumors primarily caused direct compression and injury of the sixth cranial nerve (31.6%), leading to diplopia (29.2%) in most patients. As described by Feuvret et al. [36][28], primary SBCs may also invade the anterior fossa, mostly causing vision impairment and hypopituitarism by directly compressing the optic apparatus or the pituitary stalk. However, such symptoms are non-specific and may also occur in patients with skull base chordomas and other sarcomas [8,56,57][8][29][30]. Likewise, radiological features of chordomas and SBCs may overlap, with similar localization and bone destructive patterns [58][31]. Histological confirmation is thus needed for accurate diagnosis and treatment planning.

In view of the complex anatomy of primary SBCs, management strategies require multidisciplinary approaches encompassing neurosurgery, otolaryngology, maxillofacial surgery, ophthalmology, and radiation oncology [5,56,59][5][29][32]. A stand-alone biopsy is rarely pursued, carrying surgical risks comparable to resection whilst providing limited clinical benefit [23,24,36,39][25][33][28][22]. Tumor resection is preferred, having both a diagnostic and therapeutic role. As described for skull base chordomas and osteosarcomas, the selection of the best surgical approach depends on the tumor’s bony epicenter and extension, aimed at safely exposing the lesion and the involved cranial nerves [8,56,57,60,61][8][29][30][34][35].

The endoscopic transnasal and the open frontotemporal-orbitozygomatic approaches were the most common, better addressing tumors involving the petrous apex and upper clivus and anteriorly invading the cavernous sinuses [35,39,40,43][36][22][37][38]. By contrast, retro-sigmoid and trans-petrosal approaches were performed to manage less frequent posterior fossa primary SBCs extending to the internal acoustic canal [29,31][39][40]. Of note, staged procedures were pursued in patients with large tumors not amenable to a single surgical resection [4,13,36][4][13][28]. With regards to the extent-of-surgery, different authors argued for aggressive gross total resection or safe cytoreduction with adjuvant radiotherapy, weighting surgical risks against benefits in terms of local tumor control and survival [15,25,27][15][41][42]. More recently, Patel et al. [11] analyzed the United States national cancer database and found no significant differences between partial and radical SBCs resection, but advocated functional-sparing subtotal resection followed by adjuvant radiotherapy, achieving satisfactory outcomes without sacrificing patients’ functional status. When subtotal resection is planned however, it must be done with the optimal parameters for radiotherapy in mind, to ensure the minimal number of surgeries possible without compromising optimal radiation dosing or increasing radiation complications. A minimum of 3 mm clearance from brainstem and 5 mm from optic apparatus are important guiding principles.

Adjuvant radiotherapy has emerged as a cornerstone treatment in the management of skull base chordomas and sarcomas, mainly directed against unresectable tumor portions adherent to critical neurovascular structures [8,56,57][8][29][30]. Although bone chondrosarcomas and SBCs are generally considered to be radioresistant due to their slow growth patterns, post-resection radiotherapy effectively improves local tumor control, especially in high-grade conventional subtypes or non-conventional subtypes [56,62][29][43]. Adjuvant radiotherapy was delivered with high total doses due to SBCs’ poor radiosensitivity, similarly to radiotherapy protocols for other skull base sarcomas [12,56][12][29]. In patients receiving adjuvant radiation, proton-based particle therapy, alone or combined with photon-based protocols, was preferred mostly because of the favorable dosimetric profile (the Bragg peak effect), which allows the delivery of high doses to precise tumor targets with rapid distal fall-off, likely limiting radiation injuries to critical adjacent brain regions [63,64][44][45]. The use of carbon-ion-based radiotherapy has also been described for treating skull base chordomas and chondrosarcomas, but its limited availability in a few select centers precludes a comprehensive understanding [14,27,33][14][42][46].

In patients with primary SBCs, the therapeutic goals focus on clinical improvement and local tumor control maintaining function and quality of life and minimizing treatment-related complications. We report favorable rates of symptomatic improvement and radiological tumor volume shrinking in patients receiving surgery plus adjuvant radiotherapy, with no statistical differences based on types of radiotherapy protocol. Although both treatment strategies carry intrinsic risks of severe adverse events, significantly higher rates of radiotherapy-related complications as compared to surgical-related complications [17,36,41][27][28][47].

The prognosis of SBCs is favorable, with good 5-year and 10-year rates of local tumor control and survival. Several studies also confirmed that the combination of photon/particle-based radiotherapy to surgical resection significantly improves outcomes of SBCs and other bone chondrosarcomas, achieving 5-year PFS and OS rates of 85–95% [13,17,34,36,49,51][13][27][48][28][16][18]. Hence, maximal safe resection coupled with post-surgery radiotherapy should be recommended in eligible patients, especially with large and complex tumors. Yet, the high morbidity and the declining long-term efficacy of surgery and radiation should be taken into account, encouraging the investigation of potential SBCs biomarkers targeted by genetic and immunotherapy approaches [66,67][49][50].

3. Conclusions

Primary SBCs are rare and debilitating neoplasms that often require complex and multidisciplinary treatment planning. Surgical debulking and adjuvant radiotherapy protocols show favorable rates of symptomatic improvement and local tumor control, especially in patients with large tumors not eligible for gross total resection. However, treatment-related adverse events are common, and may severely impact patients’ functional status. Novel patient-tailored systemic therapeutic options deserve further evaluation.

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