10.2.1 Introduction and Treatment

Benign or WHO grade I meningioma, when located in the skull base area, remains a challenge for complete and safe surgical resection; consequently, residual tumor remains postoperatively and there is often a significant risk of neurologic morbidity due to proximity to adjacent eloquent brain. The 2007 WHO classification, updated in 2016, did not change the grading of meningioma except to include existence of brain invasion with a mitotic count ≥ 4 that now categorizes WHO grade II or atypical meningioma.1 It was previously established that the prognosis and clinical evolution of grade I meningioma with brain invasion was like those characterized as grade II lesions.2

Skull base WHO grade I meningioma has a typically indolent onset, with minimal symptoms until tumors become large enough to compromise adjacent functional neurovascular structures. The slow onset results in a delay in diagnosis and presentation, often at an advanced stage.3 Depending on the location of the WHO grade I meningioma in the skull base, presenting deficits are usually referable to proximate cranial nerves.

Meningiomas of the skull base originate from the olfactory groove, sphenoid wing, suprasellar and parasellar regions, petroclival, cerebellopontine angle, and foramen magnum.4 Imaging is often characteristic, although radiographic findings may vary among patients. On CT, meningiomas are hyperdense and sometimes calcified. On MRI, meningiomas often are isointense with gray matter on all sequences, and contrast enhancement is intense and homogenous, although necrotic areas may be observed in large lesions.4

Meningiomas are highly vascularized tumors that have high relative cerebral blood volume (rCBV) values on MR perfusion. MR perfusion may assist in the differential diagnosis of skull-based lesions.5 ^,​ 6 ^,​ 7 Diffusion tensor imaging provides additional information about the tumor’s cellular content and may help differentiate among atypical, fibroblastic, and benign meningiomas.4 ^,​ 8 ^,​ 9 High alanine and low N-acetylaspartate peaks are observed on MR spectroscopy (MRS), but bone artifacts in the skull base often limit the use of MRS except for large lesions.10

The initial management of patients who have WHO grade I meningioma of the skull base usually consists of surgery, surgery plus radiation therapy (RT), RT alone, or observation.3 ^,​ 11 ^,​ 12 Observation is an option in asymptomatic and small lesions, those defined by National Comprehensive Cancer Network (NCCN) guidelines as having a diameter of less than 3 cm, but an observation-only approach is predicated in part on the tumor’s anatomical proximity to neurovascular structures. Surgery is recommended for symptomatic lesions whenever possible if it can be performed without sustaining functional morbidity. In instances of incomplete resection, postsurgical RT is often administered.3 ^,​ 11 ^,​ 12 Differing methods of RT may be used, including conformal external fractionated RT, stereotactic radiosurgery (SRS), stereotactic radiotherapy, intensity-modulated RT (IMRT), and volumetric-modulated arc RT.13 ^,​ 14 ^,​ 15 ^,​ 16 ^,​ 17 As of 2019, systemic treatment does not have an indication in the frontline treatment of meningioma. Particularly with skull-based WHO grade I meningioma, recurrence is frequent, and surgery or RT are most often deployed again as first salvage therapy. A variety of systemic therapies have been evaluated in surgical and RT refractory meningiomas, including chemotherapy, hormonal therapy, immunotherapy, and targeted therapies. These therapies are discussed hereafter. Regardless, most systemic treatments show modest activity. Recent identification of several molecular and druggable targets may allow development of more active systemic therapies in the future.

In all grades of meningioma, the prognosis is related to extent of resection (Simpson grade), patient characteristics such as gender (unfavorable for male), and tumor pathologic profile, such as WHO grade, Ki67/MIB-1 index, percentage of tumor cells in the S phase, p53 overexpression, telomerase activity, and telomerase reverse transcriptase (TERT) promoter mutation status (unfavorable when mutated).18 ^,​ 19 ^,​ 20

10.2.2 Pathogenesis, Genetics, Molecular, and Cellular Biology

Nearly 60% of WHO grade I meningiomas exhibit mutations of the NF2 gene on chromosome 22 (location: q12.2).21 ^,​ 22 ^,​ 23 ^,​ 24 The NF2 gene codes for the protein merlin, which belongs to the 4.1 family of structural proteins, and behaves as a tumor suppressor. Merlin is named for its similarity to moesin, ezrin and radixin-like protein. Variable levels of merlin loss are observed in different subtypes of grade I meningiomas (lower loss in the meningothelial type than in fibrous and other).25 Merlin localizes to the cell membrane and is involved in controlling cell–cell contact and cell motility.

The following proteins show some degree of interaction with merlin: CD44 and β1-integrin, βII-spectrin, paxillin, actin, and syntenin. These proteins are involved in cytoskeleton dynamics, sodium–hydrogen exchange regulatory factor, hepatocyte growth factor–receptor regulation, and endocytosis.26 Merlin downregulates the Yes-associated protein (YAP), a protein that controls cellular proliferation. NF2 mutations result in increased proliferation of arachnoid cap cells and meningioma development.27

Besides merlin loss, other protein 4.1 family members are also downregulated in grade I meningiomas. Up to 50% of WHO grade I meningiomas display a dual loss of protein 4.1B (DAL-1) and merlin expression.28 In up to 85% of sporadic meningioma, loss of TSLC-1 gene (tumor suppressor gene for lung cancer-1) is observed, triggering dysfunctional interactions between its protein and DAL-1.29 In normal conditions, the protein of the TSLC-1 gene (tumor suppressor gene for lung cancer-1) interacts with DAL-1, which is present in the plasma membrane, close to cell–cell contact points. Both proteins are spectrin–actin-binding proteins, and when they interact by direct binding, they influence cell motility through actin reorganization.30

The therapeutic targeting of TSLC-1 and DAL-1 might be part of a future strategy of anti-invasion and antimigration in meningiomas that exhibit intact expression of these two proteins.26 ^,​ 31 AKT1 mutation is found almost exclusively in skull-based grade I meningiomas and has become another potential therapeutic target since the development of AKT inhibitors.32 ^,​ 33

Multiple growth factors and their cognate receptors are observed in meningiomas and likely determine, at least in part, progression through overexpression and dysregulation. These include platelet-derived growth factor BB (PDGF-BB), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), transforming growth factor alpha and beta (TGF-alpha and -beta), SDF1 and receptor CXCR, bone morphogenic protein, insulin growth factor I and II (IGF), HER2, somatostatin, fibroblast growth factor, placental growth factor, and cyclo-oxygenase-2 Cox-2 (34–36). EGFR and platelet-derived growth factor receptor beta are both overexpressed in WHO grade I meningiomas.34

Meningiomas show alterations of chromosomes 1, 9, 10, 14, and 22, and their proliferation has been associated with mutations of genes in chromosomes 2, 4, 7, 8, 11, 12, and 16, leading to the activation of multiple signaling pathways. The most prominent ones are summarized hereafter.26 ^,​ 35 The Wnt/β catenin pathway is involved in grade I meningiomas, in which deletions of the tumor suppressor APC gene are observed.36 ^,​ 37 A third meningiomas of all grades display losses of E-cadherin function, leading to increased invasiveness and higher recurrence rates.37 The Notch pathway is an intracellular signaling pathway mediated by the transmembrane proteins Notch 1–4.38 ^,​ 39 Hes-1 is a protein that is a target of the Notch signaling pathway, and its expression is found in all grades of meningioma and related to an overexpression of the Jagged ligand, Notch 1, and Notch 2. TLE2/TLE3 are enhancers that increase the activity of the Split family (co-repressors) and that modulate Hes-1, a NOTCH signaling protein but appear to be upregulated in high-grade meningiomas only.39

The hedgehog (Hh)/patch (PTCH) pathway is involved in cell growth and is regulated by the (Smoothened) SMO gene. When Hh binds to PTCH, it activates SMO, leading to the activation of GLI transcription factors such as GLI1 (growth activator), GLI2 (growth activator), and GLI3 (growth repressor). The Hh pathway is also involved in angiogenesis, matrix remodeling, and stem cell homeostasis.26 A recent large series demonstrated that 28% of SMO mutations (L412F or W535L) and 15% of AKT1E17K mutations are seen in meningiomas of the olfactory groove.40 Among WHO grade I meningiomas, the group having SMO mutations had a significantly poorer prognosis. Meningiomas in the SMO-mutant group had an overall 36% recurrence rate, significantly higher than in the AKT1-mutant group (16%) and the “SMO and AKT1 wildtype” group (11%). All late recurrences, defined as 5 years after diagnosis, occurred in the SMO-mutant group. The authors suggest that the high frequency of SMO mutations in meningiomas arising from the anterior and medial skull base might be explained by the central role of the sonic hedgehog pathway in craniofacial development during embryogenesis. These results support the systematic determination of SMO mutations, both for prognosis and for potential inclusion of patients in future trials targeting this pathway using Hh inhibitors. The p53/pRB pathway controls the G1 to S phase cell cycle transition through the tumor suppressor gene pRB and is involved in meningioma progression and development of the anaplastic grade.26

The PI3K/AKT and mitogen-activated protein kinase (MAPK) are two pathways involved in grade II/III meningiomas only, in which high levels of phosphorylated Akt (PI3K/Akt) are found.21 ^,​ 41 ^,​ 42 ^,​ 43 ^,​ 44 Decreased levels of MAPK lead to higher recurrence rate. Other pathways, such as the phospholipase A2-arachadonic acid cyclo-oxygenase pathway, the PLC-gamma1-PKC pathway, and the transforming growth factor-beta (TGF-b)-SMAD signaling pathway, have all been related to meningioma pathogenesis.45 ^,​ 46 ^,​ 47 The levels of expression of cox-2 and of tumor necrosis factor–related apoptosis-inducing ligand receptor 4 (TRAIL-R4) seem correlated to the grade of meningioma.48 KIT expression is upregulated in 20.6% of meningiomas and is another potential druggable target.18 TERT promoter mutations, which are correlated to a decreased time to progression and a higher risk of recurrence, are present in only 1.7% of WHO grade I meningiomas.47

10.2.3 Systemic Therapies

An accurate assessment of the therapeutic efficacy in meningiomas has not been possible until recently, mainly because of the heterogeneity of response criteria used in different series. The Response Assessment in Neuro-Oncology (RANO) working group recently proposed use of the 6-month progression-free survival (PFS-6) as the standard in clinical trials in recurrent meningiomas.49 The weighted PFS-6 of WHO grade I meningioma determined by the RANO authors was 29% (95% confidence interval: 20.3–37.7%). The authors concluded that a new therapeutic compound should demonstrate a PFS-6 > 50% in WHO grade I meningioma if it is to be considered a therapy of interest.49 Nevertheless, there is still a lack of standardization regarding the optimal response criteria. Due to the complex shape of meningioma, the potential superiority of volumetric measures as compared with 2D McDonald criteria has been highlighted.50

10.3.1 Introduction to Chordomas and Treatment Overview

Chordomas of the skull base are rare, slow-growing, locally aggressive, and destructive bony tumors derived from embryonic remnants of the notochord. Chordomas located in the skull base represent a third of all chordomas and are most frequently located in the spheno-occipital region.114 Headaches and intermittent diplopia are the predominant clinical features at onset, followed by additional cranial nerves palsies that differ according to the topography of the chordoma (e.g., supra- or infraclival). Delays in diagnosis are frequently caused by nonspecific symptoms such as nasal congestion or dysphagia that are related to cranial nerve involvement but not always initially identified as being so.

CT imaging is the best technique for assessing bone destruction; it may show characteristic ring-forming calcifications.115 MRI better shows the extent of tumor, including soft tissue components and dural extension.116 Chordomas on MRI are hypo- or isointense on T1-weighted and hyperintense on T2-weighted MRI sequences. Contrast enhancement is heterogeneous, with a lobulated “honeycomb” appearance, reflecting the liquid and gelatinous mucoid components and necrotic-hemorrhagic areas.117 A fusion of CT and MRI ideally provides the most accurate assessment of the anatomical relation between soft tissue tumor components surrounding normal soft tissue and bone.

Though chordomas are classified as benign tumors, their prognosis is more akin to that of a malignant lesion, with high local recurrence rates, including systemic metastases (40% incidence overall, 12.5% from skull base chordoma), largely responsible for tumor-related lethality.118 ^,​ 119 ^,​ 120 ^,​ 121 ^,​ 122 The median survival rate is approximately 6.29 years with 5-year OS and PFS rates of 78.4 and 50.8%, respectively.114 ^,​ 121 ^,​ 123

Histologically, chordomas, like the notochord, are composed of large vacuolated physaliphorous cells surrounded by an extracellular myxoid matrix.118 ^,​ 124 Chordomas comprise three subgroups: conventional chordomas, chondroid chordomas, and dedifferentiated chordomas (i.e., those with sarcomatous transformation). Conventional chordomas, which comprise chordomatous features only, are most frequent, followed by chondroid chordomas, which comprise additional chondromatous features. Both entities share the same prognosis, unlike dedifferentiated or sarcomatous chordomas, which behave in a more malignant manner.114 ^,​ 125 Most chordomas stain positive for cytokeratin, and 80% are epithelial membrane antigen–positive. A limited number in addition are S100 protein–positive.126 ^,​ 127 ^,​ 128 Routine immunohistochemical staining for brachyury, a key transcription factor in notochord development that is overexpressed by chordomas, is a sensitive and specific diagnostic tool that also rules out cartilaginous tumors.129 ^,​ 130 ^,​ 131 ^,​ 132 ^,​ 133

The treatment of chordoma is continually evolving owing to continued progress in understanding underlying biology. Chordomas are radioresistant to standard radiation protocols and chemoresistant to classic cytotoxic therapies, in part as a result of their slow-growing kinetics. Standard radiation to the skull base is also limited by the radiosensitivity of the brainstem and other proximate intracranial neurovascular structures that increase the risk of radiation-related injury.134 ^,​ 135

For localized disease, consensus guidelines published in 2015 recommend a complete surgical resection with tumor-free margins.136 Classic open skull base approaches and less invasive endoscopic approaches are used to maximize the resection.121 ^,​ 122 ^,​ 137 ^,​ 138 ^,​ 139 ^,​ 140 ^,​ 141 ^,​ 142 When residual disease is remaining, often having a relationship to adjacent neurovascular structures, radiotherapy is recommended.143 ^,​ 144 ^,​ 145 ^,​ 146 Definitive (proton beam) RT is the preferred alternative in instances in which resection is not feasible. Recent advances in heavy particle RT, such as proton and carbon ion beam, are promising in the adjuvant setting of skull base chordomas.147 ^,​ 148 ^,​ 149 Adjuvant proton therapy, when added to maximal safe resection in skull base chordomas, led to 5-year local control rates of 75.8% and improved survival.147 ^,​ 148 Adjuvant carbon ion radiation provided similar local 5-year control rates of 70.0%.149 Image-guided IMRT (IG-IMRT) is also under evaluation for skull base chordoma.150 Cytotoxic chemotherapy or other systemic therapies have no proven efficacy and are thus not recommended in any line of treatment according to current guidelines.136 ^,​ 151 Nevertheless, several molecular therapies targeting essential pathways in chordomas are currently under evaluation and are discussed hereafter.

10.3.2 Pathogenesis, Genetics, and Molecular and Cellular Pathways

Advances in the molecular understanding of chordomas have led to the identification of promising prognostic markers and targetable pathways. These include genetic and epigenetic alterations that involve brachyury, downstream pathways, and receptor tyrosine kinases (RTKs). The brachyury or T gene located on chromosome 6q27 encodes a transcription factor essential for the development of the notochord.152 Normally silenced, brachyury is reexpressed at high levels in chordoma cells. Several lines of evidence also suggest a causative role of brachyury overexpression in chordoma formation. Further brachyury might be involved in the metastatic process by facilitating the epithelial–mesenchymal transition.153 ^,​ 154 ^,​ 155 ^,​ 156 As already mentioned, the expression of brachyury is very helpful for pathologic diagnosis, but its level does not seem correlated with prognosis.157

Other genetic alterations in chordomas include loss of p16, PTEN, CDKN2a/CDKN2b, and PDCD4.158 ^,​ 159 ^,​ 160 ^,​ 161 ^,​ 162 ^,​ 163 ^,​ 164 ^,​ 165 ^,​ 166 ^,​ 167 ^,​ 168 Losses on chromosome 1p and the FHIT gene and gains on 1q and 2p have been detected in skull base chordomas.152 ^,​ 160 Loss of chromosome 1p36, 9p loss of heterozygosity, and an elevated Ki67 proliferative index are associated with shorter OS in skull base chordomas.152 ^,​ 161 Additionally, loss of chromosome 1q, gain of 2p, and aberrant brachyury copy number are associated with recurrence.

Many alterations in the signaling pathways and growth factors are involved in chordoma biology as well. Both the PI3K/AKT/TSC1/TSC2/mTOR and STAT3 pathways are activated.162 STAT3 level of expression has reported prognostic value. Changes in EGFR signaling, activation of IGF1R, and loss of MTAP have also been identified.118 ^,​ 163 ^,​ 164

Protein tyrosine kinases (PTKs) mediate phosphorylation of selected tyrosine residues, resulting in functional activation of many proteins and thus playing a crucial role in cancer development. RTKs are specialized transmembrane PTKs that mediate signaling via sampling of the external environment. RTKs are composed of extracellular domains that bind cognate environmental ligands and of an intracellular domain that mediates the signaling event via dimerization and binding to other signaling molecules. EGFR overexpression is observed in 69 to 79.6% of chordomas and is related to tumor aggressiveness.144 ^,​ 163 ^,​ 165 ^,​ 166 ^,​ 167 PDGFR expression is also observed in chordoma. Although PDGFR promotes chordoma cell proliferation through activation of the PI3K/AKT, RAS/ERK, and STAT pathways, PDGFRβ is observed in the stromal component of the tumor and is likely involved in microenvironmental regulation.144 ^,​ 165 ^,​ 168 ^,​ 169 ^,​ 170 ^,​ 171

Increased expression of angiogenesis-related factors such as VEGF, hypoxia-inducible factor-1α (HIF-1α) and matrix metalloproteinase (MMP)-2 and -9 has been identified in chordoma tissue and cell lines.172 ^,​ 173 MMP-9 expression is correlated with higher rates of local recurrence and poor prognosis.173

Epigenetic alterations, especially modifications of the expression of microRNA (miRNA) have been identified in chordomas, and may be therapeutically targetable as illustrated in vitro.174 ^,​ 175 ^,​ 176 ^,​ 177 ^,​ 178 ^,​ 179 For example, the administration of nonselective histone deacetylase inhibitors significantly triggers apoptosis in chordomas cells.174 Similarly, the blockade of the constitutive downregulation of microRNA-1 in chordomas inhibits cellular proliferation, migratory and invasive properties, and the expression of the oncoprotein SLUG as well.176 ^,​ 177 The restoration of two constitutively downregulated miRNAs targeting EGFR, MET, and Bcl-xL block cell proliferation.175

10.3.3 Systemic Therapies

As already mentioned, cytotoxic chemotherapy has not proven efficacious and thus is not recommended in any line of treatment of chordomas. Brachyury based on its determinant role in notochord development and selective reexpression in chordoma makes this an attractive and potential target.¹⁴⁵ This is illustrated in vitro by the differentiation and senescence of chordoma cells, triggered by silencing the brachyury gene.180 Currently no treatment directly targets brachyury. An alternative approach would be instead to target downstream or interacting signaling pathways such as FGFR/MEK/ERK signal-transduction and EGFR signaling pathways.181 ^,​ 182 Immunotherapy may be promising, as illustrated by the partial responses observed in advanced chordoma patients treated with an immune-stimulating therapeutic cancer vaccine designed to elicit brachyury-specific T-cell responses.183

Multiple PTKs are posited to be involved in chordoma development and progression, some of which are functionally redundant. Therapeutic strategies comprise simultaneous inhibition of different PTKs or blocking of downstream signaling pathways. In chordomas, the PI3K/AKT/mTOR pathway is activated and PTEN is inhibited.162 ^,​ 168 ^,​ 169 ^,​ 184 It was hypothesized that therapeutic activity might be seen with inhibition of signaling mediated by EGFR and PDGFR, both of which converge on the PI3K/AKT/mTOR pathway. Some data suggest a potential therapeutic role for combined AKT and mTOR inhibitors, such as rapamycin.162

Preclinical use of the combination of a mTORC1 (rapamycin), mTOR (MLN0128), and PI3K/AKT/mTOR (PI-103) inhibitors presaged clinical activity seen with both mTOR and PDGFR as single agents in recurrent chordoma. The combined clinical efficacy of the combination of an mTOR inhibitor and imatinib in imatinib-resistant patients who had chordomas illustrates another possible strategy.184 ^,​ 185 ^,​ 186 ^,​ 187 Improved activity-based molecular profiling of a patient’s tumor and identification of specific aberrant signaling pathways is likely the most effective approach, as illustrated by the spectacular efficacy of rapamycin on tumors having aberrant mTOR-pathway signaling.188 ^,​ 189

PDGFR inhibition with imatinib mesylate (alone or combined with sirolimus) has shown some antitumoral activity in case series and one phase II trial in chordoma patients, including several who had skull base chordomas.170 ^,​ 185 ^,​ 190 ^,​ 191 An overall clinical benefit of 64% and stabilization rate of 70% were observed in advanced chordoma patients during the phase II trial.190 Sorafenib, a dual inhibitor targeting PDGF and VEGF pathways, has also been prospectively assessed in a phase II trial of patients who had advanced and metastatic chordomas.192 The response rate was low (3.7%), although the 9-month PFS was 73% and the 12-month OS 86.5%. The modest efficacy of PDGFR inhibition probably reflects the limitation of drug delivery into the chordoma and thus drug exposure.144 ^,​ 145 ^,​ 169 ^,​ 192 EGFR inhibition has also shown responses and clinical improvement in a few case series and in a single phase II trial in patients who had recurrent chordoma, including skull base tumors.145 ^,​ 193 ^,​ 194 ^,​ 195 ^,​ 196 ^,​ 197 Anti-EGFR monoclonal antibodies such as cetuximab, and EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib, and lapatinib, have been studied.145 ^,​ 193 ^,​ 194 ^,​ 195 ^,​ 196 ^,​ 197 Median PFS was 8 months in a phase II trial of lapatinib, suggesting the need for a larger trial to establish the role of this strategy.193

Inhibition of proangiogenic growth factors such as VEGF is another option for recurrent chordomas. In a small clinical series including patients who had skull base tumors, the combined use of erlotinib and bevacizumab, a humanized anti-VEGF antibody, led to disease stabilization.198 Small numbers of patients have been treated with the VEGF inhibitors pazopanib or sunitinib.120 One partial response was achieved with sunitinib, and 50% of patients benefited clinically from pazopanib, exhibiting 14- to 15-month disease stabilization. These data need further confirmation to confirm the place of anti-VEGF therapy in chordomas. Other potential therapeutic targets in chordomas, such as the inhibition of STAT3 with SD-1029, or the selective de novo purine synthesis inhibitor in MTAP-deficient chordomas, have shown promise in preclinical studies.164 ^,​ 199 ^,​ 200

Although epidemiologic data show an improvement over time in the management of chordomas, with improved survival and local control, this effect is related mostly to earlier diagnosis made possible by improved imaging techniques, to improved surgical resection using endoscopic endonasal approaches, and to recent developments in radiation techniques.118 ^,​ 121 ^,​ 136 ^,​ 138 ^,​ 139 The place of systemic therapies remains suboptimal and is confined to the recurrent setting when no other options are available. Multiple targeted therapies have been tried with modest results. These approaches need further development based on an improved understanding of the underlying molecular pathways relevant to chordoma and on the increasing use of molecular characterization of chordomas that match the molecular target with a targeted therapy.

10.4.1 Introduction to Craniopharyngiomas and Treatment Overview

Craniopharyngiomas (CPs) are rare slow-growing solid or mixed solid–cystic tumors that arise from remnants of Rathke’s pouch found along the midline from the nasopharynx to the diencephalon. These epithelial tumors commonly occur close to the optic chiasm in the suprasellar area but may also be observed within the sella, the third ventricle, and the optic system.201 ^,​ 202 ^,​ 203 ^,​ 204 ^,​ 205 CP often decrease life span and can consequently be considered low-grade malignancies. These tumors show no gender predilection and have a bimodal occurrence between 5 and 14 years in children and 50 and 75 years in adults.206

Clinical presentation is variable, depending on the tumor location, and may consist of visual acuity and field disturbances, a wide range of endocrinopathies, headaches caused by compression or hydrocephalus or meningeal spread, and depression. Growth retardation in children and sexual dysfunction in adults are the most frequent endocrine manifestations. Diabetes insipidus is also frequent. Endocrine and visual assessments, including visual field testing, are part of the systematic presurgical and postsurgical usual and customary evaluations. Neuroimaging most often shows a calcified cystic mass in the parasellar region, but both characteristics may be lacking in up to 25% of cases. Based on histological patterns, adamantinomatous and papillary CP are separate entities in the WHO classification.207 Both subtypes seem to share the same evolution in terms of treatment efficacy and survival.208 ^,​ 209

Surgery is the primary and major component of initial treatment. Surgery provides a diagnosis as well as relief of symptoms. Maximal safe resection is advocated, but cyst aspiration followed by partial resection is an alternative in some cases considering that the expected benefits of surgery should be balanced with potential surgical morbidities.

RT is indicated after partial resections and at recurrence.210 Stereotactic RT and RSR, IMRT, and proton beam RT are most often employed.210 ^,​ 211 ^,​ 212 ^,​ 213 ^,​ 214 ^,​ 215 ^,​ 216

Compressive cysts need to be addressed when causing hydrocephalus or visual or hypothalamic disturbances. Percutaneous aspiration or aspiration via an Ommaya reservoir, intracavitary irradiation with stereotactic administered radioisotopes, and intracavitary chemotherapy may be used for this purpose.217 ^,​ 218 ^,​ 219 ^,​ 220 ^,​ 221 ^,​ 222 ^,​ 223 ^,​ 224 ^,​ 225 ^,​ 226 ^,​ 227 ^,​ 228 ^,​ 229 Surgery and RT may result in a wide range of endocrine, visual, neurological, and cerebrovascular side effects that may appear early or late, depending on clinical context. These treatment-related deficits include panhypopituitarism and related complications such as obesity, diabetes insipidus, sleep and temperature regulation disorders, visual field impairment, cognitive and behavioral disorders, arterial stenosis and ischemic strokes, cerebral cavernomas and aneurysm, moyamoya syndrome, meningioma, and high-grade glioma.230 ^,​ 231 ^,​ 232 ^,​ 233

10.4.2 Pathogenesis, Genetics, Molecular and Cellular Overview

The two histologic subtypes of CP show distinct molecular genetics. Activation of the Wnt signaling pathway via activation of mutations in the gene encoding β-catenin (CTNNB1) are reported in 96% of adamantinomatous CP (ACP), a subtype of CP seen mostly in the pediatric population.234 ^,​ 235 ^,​ 236 ^,​ 237 ^,​ 238 ^,​ 239 This driver mutation leads to accumulation of the protein β-catenin, which plays a role in cell signaling and cell adhesion. The Wnt signaling pathway promotes cell proliferation and differentiation. When the Wnt pathway is activated, β-catenin localizes to the cytoplasm and nucleus and can be detected through standard immunochemistry and used as a marker of CTNNB1 mutation status.235 ^,​ 236 ^,​ 239 ^,​ 240

In one study using whole-exome sequencing, mutations of BRAF V600E oncogene were reported in 95% of papillary CP (PCP), which are commonly observed in the adult population and are not found in ACP.239 In another study using targeted Sanger sequencing, the BRAF V600E mutation was shown in 81% of PCP and in 12.5% of ACP displaying the CTNNB1 mutation as well. These data suggest that these mutations are not mutually exclusive but rather tend to be predominant in one specific subtype of CP.240 Immunohistochemistry provides the same sensitivity for detection of the BRAF V600E mutation as sequencing and is much more widely available.235 ^,​ 236 ^,​ 239 ^,​ 240 Circulating BRAF V600E DNA has been detected in blood during treatment with a BRAF inhibitor, indicating that “liquid biopsy” may become a tool in the diagnosis and response to treatment of BRAF V600E mutated CP.235 The activating mutation BRAF may serve as a potential therapeutic target.

10.4.3 Systemic Therapies

10.5.1 Introduction to Giant Cell Tumor of the Bone and Treatment Overview

Giant cell tumor of the bone (GCTB) is a rare, benign, slow-growing but locally destructive intraosseous and osteolytic tumor of skeletally mature young adults in their second to fourth decade, predominant in females and Asians. There is an increased incidence of GCTB of the skull in Paget’s disease. Although GCTB is considered a benign lesion, its evolution is unpredictable. Neurologic deficits often result from local invasive and compressive effects of the tumor. Prognosis is impacted by recurrence, malignant transformation, and the rare (< 5%) occurrence of metastases, predominantly to lungs. The local recurrence rate is high in cases of incomplete surgery, mostly within 2 years of surgery. The recommended follow-up period is 5 years only, because recurrences after that period are quite rare. Clinically, patients present with multiple cranial nerves palsies and headaches. Minimal work-up should include serum calcium and phosphorous, serum parathyroid hormone, bone scan, chest X-ray, contrast brain CT, and MRI. Additionally, some investigators advise performance of a chest CT, at least at time of recurrence, because lung metastases are most common at recurrence but on occasion may be inaugural.

A lytic lesion resulting from an intratumoral hemorrhage is evocative but not pathognomonic of the diagnosis by either skull film or CT scan.250 ^,​ 251 CT imaging is more accurate for assessment of bone architecture and MRI for the surrounding neurovascular structures. Either may show a hypervascularized and cystic lesion.252 ^,​ 253 The Campanacci classification categorizes GCTB into three grades (I, II, III), based on clinical and radiological features, but does not correlate with pathology, nor is it prognostic.254

GCTB consist of three cell-types: neoplastic giant cell tumor stromal cells, which have high proliferative activity; recruited mononuclear histiocytic cells; and multinuclear giant cells. The histologic heterogeneity of GCTB increases the difficulty of diagnosis, which is compounded by the limited sampling associated with core or fine-needle biopsies. It can be challenging to identify the atypical neoplastic stromal cells among the reactive giant cells and thus to distinguish between benign and malignant GCTB.255 ^,​ 256

Until now, surgery has been the mainstay of local treatment, achieving generally good local control rates when resection is complete. Recent advances in the understanding of the molecular pathogenesis of GCTB, and improvements in RT, have led to new and better-tolerated therapeutic options. Nevertheless, to preserve the adjacent neurovascular structures and minimize surgery-related injury, resection is often incomplete and adjuvant therapy thus required. To decrease the risk of post-RT malignant transformation, the NCCN has recommended RT as the last adjuvant option notwithstanding the established radiosensitivity of GCTB and its excellent local control rate. Stereotactic radiosurgery and IMRT have been recently used as adjuvant therapies but require further validation.251 ^,​ 257 ^,​ 258 Denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand (RANKL), was approved by the FDA in 2013 for the treatment of GCTB.255 ^,​ 256 Other systemic therapies are discussed hereafter.259 ^,​ 260

10.5.2 Pathogenesis, Genetics, and Molecular and Cellular Pathways

The proliferative fraction of GCTB is thought to be derived from the stromal compartment, but the absence of cytologic aspects of malignancy in stromal cells, combined with the lack of clonal cytogenetic structural aberrations in GCTB in most studies, suggests that these cells may be reactive and not neoplastic.261 ^,​ 262 ^,​ 263 ^,​ 264 However, neoplastic stromal cells and mesenchymal stem cells share similar differentiation characteristics. When present, the overexpression of p53 and centrosome amplification are correlated with a high risk of recurrence, and the overexpression of p53 is also associated with an increased risk of metastases. Centrosome amplification is more frequent in recurrent and malignant GCTB.265 ^,​ 266 Fifty-four percent of GCTBs have 20q11 amplifications.267 Genetic instability is also suggested by the presence of a driver mutation in H3F3A, exclusively in the stromal cells in > 90% of GCTB.268 Furthermore, telomere dysregulation is present in up to 70% of GCTB, with a telomere protective-capping mechanism permitting telomere length maintenance.269 ^,​ 270 ^,​ 271 Telomere maintenance markers such as human telomerase reverse transcriptase and promyelocytic leukemia body-related antigens are expressed by GCTB.271 ^,​ 272 ^,​ 273 A telomeric fusion in chromosomes 11p, 13p, 15p, 18p, 19p, and 21p is present in more than 80% of GCTB, predominantly in grade III tumors.274

The multinucleated giant cells in GCTB result from the recruitment of CD68-positive monocytes attracted by SDF-1 and MCP-1, which are produced by stromal cells, and by the VEGF present in the stromal environment, because these monocytes express VEGFR1 (Flt1) among other macrophage markers.250 At a molecular level, RANKL (receptor activator of nuclear factor kappa B [NF-kB] ligand) plays a major functional role in the molecular pathogenesis of GCTB. The osteoblast-like mononuclear stromal cells display a high rate of expression of RANKL.255 ^,​ 262 ^,​ 275 ^,​ 276 ^,​ 277 ^,​ 278

Receptor activator of nuclear factor-kappa beta (RANK) ligand (RANKL) interactions and macrophage colony–stimulating factor (M-CSF) stimulate recruitment of osteoclastic cells from normal mononuclear preosteoclast cells that become multinucleated osteoclast-like giant cells.279 ^,​ 280 ^,​ 281 ^,​ 282 ^,​ 283 Through a cathepsin K- and MMP-13–mediated process, these giant cells cause the characteristic bone destruction observed in these lesions.284 ^,​ 285 ^,​ 286 Runx2 may be a driver in cytokine-mediated MMP-13 expression in GCTB stromal cells.287 CCAAT/enhancer binding protein beta(C/EBPbeta), by activating RANKL promoter, seems to be a significant factor in GCTB pathophysiology.288 Given the predominant role of RANKL in the genesis of these multinucleated giant cells, the inhibition of RANKL signaling by the use of the targeted antibody denosumab has proven highly effective.

The CD33 + phenotype of the giant cells in GCTB may also in the future be targetable using an anti-CD33 antibody such as gemtuzumab.282 ^,​ 283 Some cells also are positive for PDGFA, C-kit, and EGFR, all of which can be therapeutically targeted using commercial drugs.289 ^,​ 290 The EGFR is expressed by neoplastic stromal cells and plays a role in their proliferation, in osteoclastogenesis, and likely in the progression of the disease.289

Less prominent RANKL-independent pathways are involved in GCTB osteoclastogenesis and may represent another druggable target.279 These RANKL-independent pathways include tumor necrosis factor-α, interleukin-6, tumor growth factor-β, a proliferation-inducing ligand, B-cell activating factor, nerve growth factor, insulin-like growth factor I (IGF-I), and IGF-II. Further understanding of GCTB molecular pathogenesis will further inform the development of novel molecular-based therapies.

10.5.3 Systemic Therapies

Denosumab

Denosumab is a fully human monoclonal antibody against RANKL. Its clinical benefit has been shown in phase II trials involving recurrent or unresectable GCTB.260 ^,​ 311 ^,​ 312 Reported objective response rates of 86% are seen along with a reduced need for resective surgery. Long-lasting responses are seen in most patients (96% PFS at a median follow-up of 15 months), which combined with a favorable toxicity profile (1% incidence of osteonecrosis) make denosumab the therapy of first choice in patients who have GCTB (Fig. 10.1).251 ^,​ 312

Based on results in 305 patients from two phase II trials, denosumab has been approved for patients who have unresectable GCTB or in whom a surgery would result in significant functional morbidity. NCCN guidelines emphasize indication for use of densoumab in instances of unresectable tumor. However, there are no data regarding the optimal duration or dose schedule of denosumab. Additionally, the optimal timing for the use of denosumab is also not well defined. Denosumab use has been proposed in the neoadjuvant setting, when surgery is expected to be incomplete, and when disease is clinically aggressive or is associated with a low performance status (PS) and impaired quality of life.273 The goals are to improve the resectability of the tumor by reducing its size (i.e., downstage) and to further achieve improvement in performance status (PS) and quality of life (QoL). Potential benefits in the adjuvant setting after surgery, to reduce local recurrence, is also under evaluation.312

There are limited data on the long-term safety of denosumab, especially relating to the most serious treatment-related adverse event, mandibular osteonecrosis. New challenges come with new therapies, and response assessment in GCTB is no exception. Postdenosumab treatment pathology can be challenging to interpret in some cases.313 Most often seen is a significant reduction of giant cells and neoplastic stromal cells, with some degree of bone reformation. However, cellular atypia and some patterns of ossification may suggest osteosarcoma or an undifferentiated pleomorphic sarcoma.255 ^,​ 260 ^,​ 313 Correlation of posttreatment pathology with clinical and imaging data is often necessary to achieve a correct diagnosis.

Although the role of (18F-FDG) PET scanning is not clear at time of diagnosis in GCTB, FDG-PET does appear to be a sensitive marker of early response to denosumab, as changes in standardized uptake values reflect tumor metabolism and angiogenesis.314 ^,​ 315 ^,​ 316 ^,​ 317 Nevertheless, MRI should not be replaced by FDG-PET; rather, the latter provides correlative information that may augment MRI findings.

The introduction of denosumab has profoundly altered the management of GCTB of the skull base, providing a new treatment option that augments surgery. However, because many questions remain unanswered regarding the practical aspects and timing of denosumab treatment, further prospective randomized trials are needed.