Current Concepts in the Management of Tumors of the Skull Base

Akio Morita, MD, Laligam N. Sekhar, MD, and Donald C. Wright, MD

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Approaches to the management of cranial base tumors, including surgery, radiotherapy, chemotherapy, hormonal therapy, and combinations of therapy, are individually tailored according to anatomy, tumor classification, and biologic aggressiveness.

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Background:  Due to their involvement with critical neurovascular structures, tumors located in the cranial base present challenges to neurosurgeons and are associated with high morbidity and mortality.
Methods:  Rates of tumor control, complications, patient outcomes, and recurrences were extracted and summarized from two decades of our surgical and radiological treatment follow-up and review of the medical literature.
Results:  Recent advances in surgical techniques involving cranial base approaches have made surgical intervention safer and curative resection more likely.  In managing benign tumors, surgical resection is the gold standard for treatment.  While immediate complications are still significant, long-term outcomes in most cases are excellent.  Focused radiosurgery using a gamma knife or linear accelerator has produced favorable outcomes, and it improves the management of small or minimally symptomatic cranial base tumors.  For slow-growing malignant tumors, extensive surgery followed by radiotherapy achieves the best outcome.  In managing highly malignant tumors, outcome is determined by the effects of chemotherapy and radiotherapy.  On some occasions, surgery is needed to obtain greater control of highly malignant tumors.
Conclusions:  Skull base tumors are relatively common, and management of these tumors is rapidly evolving.  The combination of surgical excision using cranial base techniques, radiosurgery, fractionated radiotherapy, and chemotherapy should be individually tailored based on the location and pathological aggressiveness of the tumor and the symptomatology of the patient.

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Introduction

    Management of tumors in the cranial base has been challenging for neurosurgeons and other medical specialists for more than a century.¹ Since tumors are located deep in the skull and can involve important neurovascular structures, surgical treatment was associated with high morbidity and mortality. Until recently, radiation therapy was the standard palliative measure. However, during the 1970s and 1980s, neurosurgeons and head and neck surgeons^2-4 introduced advances in surgical instrumentation and developed new approaches to the cranial base. Simultaneously, focused stereotactic radiotherapy was introduced to treat localized tumors in a more refined manner.⁵ With this combination of modern techniques, recent management of skull base tumors has dramatically improved.⁶

General Concepts

Classification and Management

    Various types of tumors involve the skull base. As depicted in Table 1, the most frequent types of tumors treated in our institutions are meningiomas, pituitary adenomas, and schwannomas. However, the numbers can be significantly influenced on a referral basis. In general, we can classify and discuss the management of the cranial base tumors according to their individual histopathologic types. Since there are numerous types of tumors, we have limited their classifications to three groups based on biologic aggressiveness, and in nine territories based on their location. This classification system not only simplifies our choice of treatment modalities, but also clarifies our understanding of the pathophysiology in clinical presentation. Biologic aggressiveness directs our decision on which mode of treatment is the best from an oncological standpoint, and the location of tumor and clinical presentation provide information on the risks that are involved in treatment.

Table 1. -- Cranial Base Tumors Treated at The George Washington University Medical Center (1993 to August 1997)
Types of Skull Base Tumors	Numbers of Cases
Meningiomas	356
Pituitary adenomas	133
Schwannomas	94
Chordomas	37
Chondrosarcomas	19
Craniopharyngiomas	14
Glomus jugulare tumors	14
Epidermoid cysts	13
Cholesterol granulomas	10
Fibrous dysplasia	8
Hemangiomas in cavernous sinus	7
Other benign tumors	6
Carcinomas of the skull base	19
Other malignant tumors	4
Total	734

Biologic Aggressiveness

    We group skull base tumors in roughly three pathologic entities: benign, slow-growing (low-grade), and fast-growing (high-grade) malignancies. Table 2 shows examples of each category.

Table 2. -- Classification of Histologic Types of Cranial Base Tumors

Benign Tumors:

Meningiomas

Schwannomas

Pituitary adenomas

Paragangliomas

Hemangiomas in cavernous sinus

Epidermoid cysts

Juvenile angiofibromas

Fibrous dysplasia

Cholesterol granulomas

Intermediate Malignant Tumors (Low Grade, Slow Growing):

Chordomas

Chondrosarcomas

Adenoid cystic carcinomas

Low-grade esthesioneuroblastomas

Highly Malignant Tumors (Fast Growing):

Carcinomas (adenocarcinoma, squamous, transitional, undifferentiated)

Sarcomas (rhabdomyosarcoma, Ewing's sarcoma, fibrosarcomas)

Higher-grade esthesioneuroblastomas

Lymphomas

Myelomas

Metastasis

    Benign tumors grow in an expansive fashion and induce clinical symptoms by exerting pressure on certain neurovascular structures. Hence, the reduction of the mass effect and, if possible, the complete excision of tumors are the gold standard in treating such lesions. Usually, symptoms caused by the mass effect can resolve fairly quickly. However, there are always associated surgical risks that may depend significantly on the location and extent of the tumor. With the recent development of diagnostic techniques, asymptomatic or minimally symptomatic tumors are being discovered in the skull base. With benign tumors, treatment modalities should be chosen based on observation, the excision of the tumor by surgery, or the control of tumor growth by stereotactic or conventional radiotherapy. The long-term benefits and risks of each procedure and the natural history of various tumor should be carefully assessed.^7,8

    Slow-growing malignancies such as chondrosarcomas, chordomas, low-grade esthesioneuroblastomas, and adenoid cystic carcinomas are best treated with a combined mode of surgical debulking and radiotherapy.^9-11 Sensitivity to radiotherapy is variable with each tumor type. Surgical resection should be as complete as possible, especially with radioresistant tumors such as chordomas. Cranial base approaches are useful to facilitate such procedures because they provide the surgeon with an excellent view from which to remove tumors and involved bones. Radiotherapy can involve either fractionated or focused radiosurgery depending on the size and extent of the tumor. Focused heavy particle irradiation is reported with a favorable outcome in cases with chordomas and chondrosarcomas.¹²

    Highly malignant tumors can be removed en bloc if the process does not involve critical structures. However, in most situations, piecemeal resection or sacrifice of a significant structure may be involved in surgical resection. Hence, radiotherapy with or without chemotherapy is the main treatment modality when the cranial base approach to a tumor may cause the loss of sensitive cranial structures.

Tumor Location

    Tumor location significantly affects our surgical strategy. Table 3 summarizes the classification of location, the frequently encountered tumors in each site, and the involved neurovascular structures and symptoms. The tumor’s relation to adjacent structures such as the optic apparatus should be considered. Tumors involved in more than one territory can present more complex problems. Because of the complexity in anatomical structures, the cavernous sinus (parasellar) and the petroclival areas are the most frequently discussed territory for the management of the skull base tumors.

Table 3. -- Skull Base Territories, Common Tumors, Involved Structures, and Clinical Presentation
Skull Base Territory		Common Tumors	Involved Structures and Clinical Presentation
Anterior Cranial Base
	Central	Meningioma	Olfactory nerve
		Encephalocele	Frontal lobe dysfunction (personality change)
		Nasal paranasal carcinoma	Increased intracranial pressure
		Esthesioneuroblastoma	Vision changes
			Nasal discharge
			Obstruction
	Lateral	Fibrous dysplasia	Orbit
			Vision changes
			Superior orbital fissure involvement
			Exophthalmos
Middle Cranial Base
	Central	Pituitary adenoma	Pituitary
		Meningioma	Hypothalamus (hormonal changes, diabetes insipidus)
		Craniopharyngioma	Optic nerve
		Sphenoid cancer	Chiasm
		Mucocele
	Paracentral (cavernous)	Meningioma	Optic nerve in apex
		Schwannoma	Cranial nerve 3-6
		Cavernous hemangioma	Temporal and frontal lobe
		Chordomas	Cavernous carotid artery
			Facial pain
			Diplopia
	Lateral	Meningiomas	Trigeminal divisions
		Schwannoma	Lateral orbit
		Juvenile angiofibroma	Infratemporal fossa
		Adenoid cystic carcinoma
Posterior Cranial Base
	Upper central (petroclival-clival)	Meningioma	5th and 6th nerve
		Schwannoma	CN 3, 4, 7, 8, 9 (10th if progress)
		Epidermoid	Pons
		Chordoma	Cerebellum and hydrocephalus
		Chondrosarcoma	Carotid
		Cholesterol granuloma	Basilar artery
		Cholesteatoma
	Lower central (foramen magnum)	Meningioma	11th, 12th nerve
		Schwannoma	Lower cranial nerves if progress
		Chordoma	Various degree of sensorimotor long-tract sign (weakness, stereoagnosis, cape shape anesthesia in neck, dysesthesia and atrophy of hand)
	Upper lateral (CP angle)	Schwannoma	7th and 8th nerve (often involved)
		Meningioma	5th and lower cranial nerves
		Lipoma	Pons and cerebellum
		Epidermoid
	Lower lateral (jugular foramen)	Schwannoma	9th-11th nerve
		Paraganglioma	12th nerve (if involving retropharyngeal space or occipital condyle)
			7th/8th nerve in EP angle or temporal bone
			Tinnitus
			Dysphagia

Diagnostic Studies and Interventional Radiological Treatment

    Diagnostic studies for skull base tumors include magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), computed tomography (CT) scans, bone window and three-dimensional (3-D) CT scans, and angiography. MRI is currently an essential test to show the nature and extent of the tumor. Tumor appearance on T1- and T2-weighted images and gadolinium-DTPA enhancement characteristics are the most important factors in making differential diagnoses and in determining the location of the tumor, the type of bony destruction, and/or the calcification shown by a CT scan. Bone window and 3-D CT scans are useful in determining surgical approaches and in deciding what areas of the cranium should be drilled to best expose the tumor. Angiography is being replaced with MRA and the 3-D CT to show the major arterial anatomy. However, angiograms are still superior in revealing the venous anatomy and blood supply to the tumor, which often influence the surgical and treatment approach. A balloon occlusion test is essential when the sacrifice of a major cerebral artery is anticipated during surgery.⁶

    Interventional radiological techniques (eg, selective embolization of tumor arterial supply) are useful in reducing blood loss in the removal of vascular tumors. It has also shown effectiveness in delivering chemotherapeutic agents directly to the tumor.

Principles for the Treatment of Cranial Base Tumors

    For patients presenting with skull base tumors, treatment options include observation with close follow-up, operative excision, radiotherapy, chemotherapy, or a combination of these therapies.

Observation

    For those skull base tumors that are suspected to be benign, observation is a reasonable option, particularly when the patient has minimal symptoms. Skull base meningiomas and schwannomas are the most typical examples. Careful follow-up, including physical examination and imaging studies, is important in detecting changes and in following the progress of the tumor. However, while small tumors can be treated with minimal risks, larger tumors are more difficult to treat and may cause significant posttreatment problems.

Surgery

    Since cranial base tumors are deep in location and surrounded by critical structures, conventional neurosurgical approaches are disadvantageous because of the need for significant brain retraction, poor control of the lesion and adjacent structures, and often suboptimal exposure. In the past, such operations often resulted in partial resection of the lesion with high morbidity. However, modern skull base surgery provides better exposure of deep-seated cranial base lesions with less cerebral retraction by combining the removal of noncritical osseous structures (eg, petrous apex, clinoid) with specialized operative maneuvers (eg, tentorium resection, partial labyrinthectomy, mobilization of neurovascular structures). With the introduction of these techniques, most skull base tumors can be safely approached, and many are radically resected. Many cavernous sinus and petroclival tumors that were previously thought to be inoperable have been successfully removed.

    Modern skull base surgery carries certain risks. Because these approaches require extensive bone removal and often necessitate entrance into or transgression of potentially contaminated spaces (eg, the paranasal sinuses), the potential exists for complications such as cerebrospinal fluid (CSF) leakage, infection, cosmetic defects, and cranio-vertebral instability.¹³ The exposure or manipulation of neurovascular structures also carries risks for stroke or cranial neuropathies. The operative time and extent are increased and pose risks for perioperative medical problems such as pneumonia, hormonal and electrolyte disturbance, coagulopathy, and pulmonary embolus. CSF leakage complicates cranial base surgery in 5% to 30% of cases,^9,13,14 whereas major neurological complications have occurred in 4% to 10% of cases. Operatively induced cranial neuropathies occur in 10% to 96% of cases, depending on the region of surgery, the nature of the tumor, and the aggressiveness of resection.³

    In cases where the carotid or vertebral arteries are involved by tumor, special consideration for preservation or reconstruction of these vessels is required.¹⁵ Injury to the venous circulation of the brain can be as devastating as an arterial injury. Such injuries can be avoided in most patients, but when they occur, immediate reconstruction is recommended. Due to the potential for major morbidity associated with skull base surgery, an experienced treatment team should carefully determine the indication for and the extent of resection, and the benefits, risks, and ultimate goals of the procedure should be thoroughly discussed with the patient.^7,8,16

Radiotherapy

    Conventional fractionated radiotherapy has been used primarily for malignant skull base tumors and radiosensitive tumors of the intermediate malignant type.¹⁷ Radiation therapy also reduces the growth and recurrence rates of some of the benign tumors including paragangliomas¹⁸ and meningiomas.^19,20 Heavy particle beam focused radiotherapy has been advocated for tumors such as chordomas and chondrosarcomas, which are known to be radioresistant. Initial results have shown efficacy, but long-term follow-up in a large number of patients is lacking.¹² High-intensity, focused radiotherapy (gamma knife or linear accelerator radiosurgery) is effective in reducing the growth rate of benign or intermediate malignant tumors.^5,21 Experience with this modality is rapidly accumulating, but definite limitations exist with this therapy, and the relationship of tumor size, configuration, and long-term efficacy remain to be defined. The results of these different types of radiotherapy for various pathologies are presented in Table 4. Although complications of radiotherapy are often reported as minimal,^{6,12,17,19,22-26} delayed complications can occur such as parenchymal injury, pituitary dysfunction, visual changes, and/or de novo radiation-induced tumors in 22 of 58 patients (38%) treated with radiotherapy for benign intracranial tumors.²⁷ Therefore, careful long-term follow-up of irradiated patients is necessary.

Table 4. -- Outcome of Radiotherapy for Skull Base Tumors
Tumors	Mode and Follow-Ups	Total Cases	Tumor Shrinkage	Tumor Control (No Growth)	Progression	Complications	Clinical Improvements	Reference
Meningioma	Fractionated after subtotal resection	140		89% 5-yr 77% 10-yr				Goldsmith et al, 1994 (19)
Meningioma	Gamma knife: 6-68 mos	88	45 (51%)	41 (47%)	2 (2%)	11 (13%)	15 (17%)	Morita et al, 1997*
Schwannoma	Gamma knife: 3-36 mos	92	23%	74%	3%	30%	4 (4%)	Linskey et al, 1992 (25)
Pituitary Adenoma	Fractionated radiotherapy non-functional	112		97% 5-yr 89% 10-yr			1 (1%)	Flickinger et al, 1989 (22)
Pituitary Adenoma	Gamma knife: 6-59 mos (24.5)	24	10 (42%)	13 (54%)	1 (4%)	5 (21%)	12 (50%) endocrine	Morita et al, 1997**
Paraganglioma	Fractionated: 1-30 yrs	599		544 (91%)	55 (9%)			Morita et al, 1997 (26)
Paraganglioma	Gamma knife 65 mos (20)	9	1 (8%)	8 (92%)	0	0		Foote et al, 1997 (24)
Chordoma/Chondrosarcoma	Proton beam: 4-119 mos (51)	80		63% 5-yr (chordoma) 78% 5-yr (chondrosarcoma)				Castro et al, 1994 (12)
Esthesio-neuroblastoma	Fractionated after surgical treatment	49		86% (with radiation) 73% (surgery alone) 5-yr local control				Foote et al, 1993 (23)
Paranasal Carcinoma	Fractionated	82		62% 5-yr  56% 10-yr disease-free				Hoppe et al, 1976 (17)
* Presented in 3rd Congress of International Stereotactic Radiosurgery Society Meeting
** Presented in 8th International Leksell Gamma Knife Society Meeting

Chemotherapy and Hormonal Therapy

    Chemotherapy is indicated in specific malignant tumors. Cisplatin is effective in treating epithelial carcinomas and has been associated with significantly improved clinical outcomes.²⁸ Other chemotherapeutic agents such as cyclophosphamide, vincristine, and doxorubicin have been administered to treat a variety of cranial base malignancies. Bromocriptine is effective in treating prolactinoma, often with dramatic reductions in tumor size and in improved long-term control. Hormonal therapy for meningiomas and juvenile angiofibromas, which often carry a hormonal receptor, is still in the investigative stage.²⁹ Interferon, somatostatin analogues, monoclonal antibodies, and gene therapies are likewise considered experimental.

Combinations of Therapy

    To obtain the maximum effect of treatments, various combined treatment regimens are indicated for the management of certain skull base tumors. For incompletely resected meningiomas, radiotherapy is effective in delaying the rate of growth and symptomatic recurrences. In esthesioneuroblastoma, there is evidence that patients benefit from a combination of preoperative or postoperative chemotherapy and radiation therapy.³⁰ A combination of chemotherapy, radiotherapy, and en bloc surgical resection has been advocated for nasopharyngeal carcinomas. Improved outcomes for cranial base sarcomas have been achieved with a combination of radiotherapy and chemotherapy. A multidisciplinary skull base tumor team should consider all treatment alternatives for patients with cranial base tumors, and the therapeutic regimen should be tailored to each individual case. The final therapeutic decision must take into account the patient’s condition, the natural history of the tumor, and the risks and benefit of each treatment option.^7,8 Carefully controlled long-term outcome studies will be of particular value in future treatment plans.

Treatment Outcome of Tumors in Specific Locations

Cavernous Sinus Tumors

    The cavernous sinus, the parasellar area, and/or the medial middle fossa can be invaded by meningiomas, schwannomas, hemangiomas, chordomas, and/or other neoplasms. Clinical presentation varies based on the extent of the tumor but usually includes the involvement of cranial nerves 2-6, seizures, symptoms of brain compression and, occasionally, brain ischemia. Because of the vital importance of these neurovascular structures, the surgical approach to this area is technically demanding, and surgical complications are relatively frequent. Table 5 depicts a recent surgical series of cavernous sinus tumors treated with cranial base approaches. Major complications such as intracranial hematomas were seen in approximately 6% to 16% of all cases; worsening cranial neuropathy was seen in 16% to 35% of all cases, and cerebrospinal fluid was seen in up to 28% of all cases. These risks are higher with a history of previous surgery and radiotherapy. However, most of these complications are temporary, and many can be treated successfully. Complete resection could be achieved in 77% of all cases, and the recurrence after a complete resection is less than 9% in all cases with a follow-up period of one to 12 years.^14,16,31,32 When the carotid artery is invaded by tumor, the artery can be reconstructed with minimal morbidity using a saphenous vein graft (Figs 1A-D). The sacrifice of the oculomotor nerve and the trigeminal nerve can rarely be achieved without significant postoperative deficit. Therefore, the preservation of these nerves is important during surgery.

Table 5. -- Outcome of Surgical Treatment of Cavernous Sinus Tumors
Authors, Year (Ref)	Case No.	Follow-Up	Total Resection	Surgical Mortality	Mortality Morbidity	New or Worse CN Deficit	CSF Leakage	Outcome % Self Care	Recurrence
Dolenc et al 1987 (14)	63 (4 malignant lesions)	2-5 yrs	45 (71%)	4 (6%)	4** (6%)	12 (19%)	5 (8%)	46 (73%) returned to previous job	3 (5%)
Sepehrnia et al 1991 (32)	54 (3 malignant lesions)	4-110 mos (28)	42 (78%)	2 (4%)	NA	10 (19%)	NA	NA	7 (13%)
DeMonte et al 1994 (31)	41 meningiomas	2-12 yrs (12 >5 yrs)	31 (76%)	3 (7%)	3 (7%)	6% worse 10% new neuropathy	2 (5%)	23 (61%)	3 (7%)
Cusimano et al 1995 (16)	124	1-97 mos (mean 29 mos)	100 (80%)	2 (2%)	20 (16%)	44 (35%) worse binocular vision	35 (28%)	93 (75%)	12 (10%)
Total	282	--	218 (77%)	11 (4%)*	27/228 (12%)	66/241 (30%)	42 (18%)	162/228 (71%)	25 (9%)
* 5 other tumor-related and 5 non-tumor-related deaths in follow-up.
** Includes carotid artery sacrifice and optic nerve damage.

    Our recent experience with cavernous sinus tumor surgery indicates markedly improved results and reduced complication rates in previously untreated lesions.³³ The development of focused stereotactic radiotherapy has provided another useful tool to control tumor growth with minimal complications (Table 6).^34,35 It rarely shrinks the tumor to a significant degree and does not reduce the mass effect. Due to the dangers of precipitating neurologic compromise or collapse by radiation-induced swelling in larger tumors, the size of treatable tumors should be less than 2.5 cm. This size limitation restricts a radiosurgical treatment approach to approximately one half of the patients in our surgical series, since the mean diameter of tumors in the majority of the surgical series is approximately 3.5 cm. The follow-up period for most gamma knife series is less than five years, an insufficient length to discuss the long-term benefits. The authors believe that microsurgery and the combination of microsurgery and radiosurgery should be offered to patients with cavernous sinus tumors on the basis of tumor characteristics, patient age, occupation, and goals.

Table 6. -- Outcome for Benign Cavernous Sinus Tumors Treated With Stereotactic Radiosurgery
Authors, Year (Ref)	Number of Patients	Margin Dose (Gy)	Follow-Up (mos)	Tumor Shrinkage (Mild)	Control	Tumor Growth	Complications (includes vision change, hearing loss)	Clinical Improvements
Duma 1993 (35)	34	10-20 (16)	6-49 (29)	19	15	0	4	24%
De Salles 1993 (34)	14***	14-25 (16.5)	3-18 (10)	8	2	4	1	70%
Ebara 1995*	12	12.2+/-1.4	6-26 (15)	5	6	1	0	25%
Kobayashi 1997**	27	Mean 13.6	Mean 26.2	21	4	2	2	11-90%
Kurita 1997**	17	NA	34.8	6	10	1	1	NA
Prasad 1997**	77	9-20 (15)	12-72	52	24	1	0	NA
Total	181			111 (61%)	61 (34%)	9 (5%)	8 (4%)	11-90%
* Personal communications
** From abstracts in the 8th International Leksell Gamma Knife Society Meeting
*** Includes 3 malignancies

Petroclival Tumors

    Petroclival tumors can involve the supra- and infra-tentorial territory. These present another challenging area for surgeons because of their deep location. Traditional neurosurgical approaches usually do not expose the full extent of the tumor adequately because of the tendency to locate above and below the incisura. Meningiomas, schwannomas, chordomas, and chondrosarcomas are common tumors of this area that may extend to other regions, from the cerebellopontine angle to the cavernous sinus. These lesions can induce brain stem and cerebellar dysfunction and neuropathy of cranial nerves III-VIII. Operative approaches using cranial base techniques have significantly improved patient outcomes, and recent clinical series show a minimal mortality rate and increasingly higher resection rates. Figs 2A-B show the complete removal of a trigeminal schwannoma using the petrosal approach. Before the 1970s, even though a subtotal resection was done in most cases, the surgical mortality rate after the resection of petroclival meningiomas was close to 50%. Our recent surgical experience with 75 petroclival meningiomas showed that a total resection was performed in 60% of cases; the mortality rate was 0%, and more than 70% of the patients returned to work.⁴ Focused radiotherapy is also used for these lesions, and a tumor control rate of more than 94% has been reported.^5-7 Due to the uncertainty of the biologic effects of radiosurgery, this type of treatment should be used conservatively on younger and healthier patients. On the other hand, this technique is very useful when managing lesions of high surgical risk in elderly patients and in patients who are in poor health. It may also be useful for patients with tumor remnants after extensive microsurgical resection.

Individual Tumors

Meningiomas

    Meningiomas are the most common neoplasms of the skull base. While meningiomas are benign and well-demarcated tumors, they have complex, special problems when they originate in the skull base area. Meningiomas can induce bony hypertrophy, and involved bone and dura can become very thick in the skull base, making it difficult to eliminate all of the tumor. They can also invade the arteries and cranial nerves of the cavernous sinus, and they can invade the pial layer of the brain stem and engulf cranial vessels. Our recent studies revealed that the tumor size, invasion of the pia mater, and previous surgery or radiotherapy significantly influence surgical outcome.⁴ In cases with tumor encasement and invasion to these vessels, we have developed techniques to reconstruct carotid and/or vertebral arteries using saphenous vein grafts.¹⁵ With these procedures, we have not seen any recurrence of tumor in the cavernous sinus for up to nine years. As discussed earlier, stereotactic radiosurgery (gamma knife) as well as fractionated radiotherapy have been used to control tumor growth with a high success rate.⁵ This mode of treatment can be useful in managing recurrent tumors, tumors involving brain stem perforators, and minimally symptomatic tumors in patients with poor health.³⁶

Schwannomas

    Schwannomas often originate from the sensory component of the vestibular, trigeminal, and lower cranial nerves, but they can also originate from the other cranial nerves including the abducens, oculomotor, and hypo-glossal nerves. In the cranium, the most common schwannomas are vestibular schwannomas, followed by trigeminal, jugular, and facial nerve schwannomas. In the cervicomedullary junction, C1-2 schwannomas can present with foramen magnum syndromes. Schwannomas are benign tumors that usually present with symptoms related to the involved cranial nerves, as well as cerebral, cerebellar, and brain stem compression. If the tumor presents with a mass effect, treatment should involve surgical resection. Recent surgical series on vestibular, trigeminal, and jugular foramen schwannomas stress the importance of surgical approaches that do not damage the surrounding nervous structures. Morbidity associated with surgery has been decreasing, and the preservation of the function of cranial nerves is improving. In a recent surgical series of vestibular schwannomas,³⁷ functional preservation of the facial nerve (House-Blackman grades 1 and 2) was achieved in 79% to 95% of all cases, depending on tumor size. Hearing can be preserved in 35% to 50% of cases where patients had preoperative hearing when the tumor size measured less than 2 cm in the cerebellopontine angle. For cases that present with a minimal mass effect or with minimal symptoms, the management options of observation, surgery, or radiation treatment should be considered.³⁸ The experience of radiation therapy, especially radiosurgery, has increased dramatically during the last decade, and the success rate of tumor control is high. In initial reports of radiosurgery on vestibular schwannomas, complications included cranial neuropathy consisting of 30% delayed facial paresis, 50% hearing loss, and 33% trigeminal neuropathy.²⁵ Recently, the result has been revised with better outcomes achieved with a new dosimetry plan. However, it is not clear if a lower dose will result in the same rate of tumor control. Additionally, patients who have recurrent tumors after radiosurgery experience worse outcomes with microsurgery.¹⁰

Pituitary Adenomas

    Pituitary adenomas are histologically benign tumors that originate in the sella turcica. They can be either hormonally active (adrenocorticotropin, prolactin, growth hormone, thyroid stimulating hormone, etc) or inactive. If the tumor presents with hypersecreting symptoms, it tends to be diagnosed early. Microadenomas and macroadenomas that are not invasive can be successfully treated by surgery and cured. However, if a tumor is large, especially if it extends into the cavernous sinus, it acts as a locally invasive tumor, and a surgical cure is less likely. The primary treatment of pituitary adenomas is microsurgery. Transsphenoidal surgery, endoscope-assisted surgery, and cavernous sinus surgery are various surgical options. Residual or recurrent tumors can be treated with radiation therapy. Flickinger et al²² reported tumor control using fractionated radiotherapy for nonfunctioning adenoma with progression-free survival rates of 97% at five years, 89% at 10 years, and 76% at 20 years posttreatment. Radiosurgery has also been introduced to manage this tumor with a high tumor control rate. However, since the tumor is located in the proximity of the optic apparatus, special consideration for the dosimetry is required. Hormonal control is achieved in 30% to 80% of growth hormone adenomas and 30% to 70% of ACTH-secreting adenomas with this technique.²¹ Multiple medical modalities have been developed and introduced to suppress abnormal hormonal secretion.³⁹ Bromocriptine is a well-established medical treatment for prolactinomas, and Octreotide (somatostatin agonist) is reported to be useful in reducing the growth hormone level and shrinking the tumor in 50% to 60% of cases.⁴⁰

Glomus Jugulare Tumors

    Glomus jugulare tumors are benign tumors originating in the temporal bone and jugular foramen. They can involve the lower cranial nerve and the auditory apparatus, and they may extend intracranially, causing brain stem compression. With surgical approaches involving otological and neurosurgical techniques, gross total resection can be achieved in 70% to 80% of cases.¹⁸ Surgical resection involves risks for the lower cranial nerves (10% of patients suffer permanent damage) and the facial nerves (14% of patients suffer permanent damage). However, long-term results show excellent patient survival and outcome, with a majority of cases alive with a Karnofsky score of >70.²⁶ Radiation therapy and radiosurgery also have been reported with high tumor control rates (90%) for one to 30 years of follow-up, but histopathologic and angiographic studies showed viable or vascular tumor in the radiated tumor mass.²⁴ Biologic effects of radiation on paragangliomas are uncertain. Recurrence after radiotherapy is difficult to treat with surgery, and the risks and complications are higher.

Chordomas and Chondrosarcomas

    Fifty percent of chordomas originate in the sacrococcygeal area, with 35% originating in the skull base territory. They account for only 1% of intracranial tumors. Chordomas often involve the clivus and adjacent area. The most frequent presentations are cranial neuropathy (abducens, trigeminal, and oculomotor), gait ataxia, and headache. Chordomas are very peculiar tumors with prominent variability in their clinical progression. Multiple studies have been conducted to identify the factors that can indicate the potential for progression.^41-43 So far, the age of presentation (>40 years of age), large tumor size, the pathologic picture with necrosis, spindle cells, and nonchondroid variants have been reported as detrimental prognostic factors. Chondrosarcomas are often difficult to distinguish from chordomas, except that their locations tend to be paramedian, often in the petrosal bone. This tumor can be graded 1-3 or mesenchymal by histopathologic findings that significantly influence the tumor’s progression. In the skull base, most tumors are grade 1 or 2.

    Both chordomas and chondrosarcomas are relatively radioresistant, and surgical resection is the most effective mode of treatment. Our recent study⁹ showed a statistically significant difference in survival between cases with total or near total resection vs subtotal or partial resection. Five-year recurrence-free survival rates in each group were 84% and 64%, respectively. Cranial base operative approaches have been useful to facilitate total resection. Previously operated tumors were difficult to remove safely and had a higher recurrence rate. Chondrosarcomas have a longer survival interval than chordomas, with five-year recurrence-free survival rates that measured 90% and 65%, respectively, after surgical intervention. Treatment with heavy particle irradiation has been reported from several institutions with favorable outcomes. Five-year recurrence-free survival rates were 78% for chondrosarcomas and 63% for chordomas with this mode of treatment.¹² This involved a selected population of patients who have survived surgical resection and have not undergone prior radiotherapy.

    No large clinical trials were attempted for chemotherapy, but several case reports demonstrate clinical improvement using vincristine, cyclophosphamide, and actinomycin D. At this time, radical surgical resection with or without radiotherapy should be the primary treatment. New chemotherapeutic regimens and new modalities of treatment such as gene/viral therapy should be developed in the future to improve outcomes.

Adenoid Cystic Carcinomas

    Adenoid cystic carcinomas are slowly progressive malignancies that originate in the minor or major salivary glands. Although adenoid cystic carcinomas constitute only a small portion of the total number of malignancies below the skull base (1%), their specific tendency to invade into the cranial nerves and spread along the nerves often requires special attention. Since this tumor presents with a long, indolent clinical course, radical treatment should be employed over palliative measures, even after tumor invasion of the cranial base. Surgical resection and radiation therapy followed by radiotherapy provide the most effective measure. Cranial base techniques are useful in achieving radical resection.¹⁰ In managing tumors that have invaded into the cavernous sinus, carotid artery reconstruction is recommended to achieve safe surgical resection. The mean survival time after the surgical resection of these tumors in the skull base is five to 10 years.⁴⁴

Esthesioneuroblastomas

    Esthesioneuroblastomas are intermediate malignant tumors originating in the anterior cranial base. They occur in the upper third of the olfactory epithelium and frequently invade into the olfactory cribriform plate. Common clinical presentation includes nasal obstruction and epistaxis. Histologic grading devised by Hyams and the tumor extent staging devised by Kadish were reported to be the prognostic factors.^11,45 Our clinical studies¹¹ revealed that tumor survival is best ensured with gross total resection with or without radiotherapy for low-grade tumors. Radiation was effective in improving the local control rate.²³ Cranial base approaches involving the craniofacial or frontobasal approach are essential to accomplish safe resection in this territory. However, for high-grade tumors, the five-year survival rate of 40% was significantly lower than the low-grade tumor five-year survival rate of 80%. In these cases, preoperative and postoperative chemotherapy should be useful. Recent studies at the University of Virginia showed the effectiveness of preoperative chemotherapeutic agents such as cyclophosphamide, doxorubicin, and vincristine. Eden et al³⁰ reported five-, 10-, and 15-year survival rates of 78%, 71%, and 65%, respectively.

Other Skull Base Malignancies

    Various types of malignancies can involve the cranial base. Nasopharyngeal carcinomas, rhabdomyosarcomas, osteogenic sarcomas, and lymphomas are the most common malignant lesions in the skull base. In most of these cases, surgical resection preceded or followed by chemotherapy and/or radiation therapy is recommended and provides the best outcome. In some anterior cranial base lesions, including rhabdomyosarcomas and nasopharyngeal cancers, en bloc resection is necessary to achieve the best oncological control. Because of a risk of associated morbidity, tumors involving the temporal or occipital bones are not good candidates for radical surgical resection, except under special circumstances. Surgical aggressiveness should be tailored according to the radiosensitivity of the tumor. Radiosensitive tumors can be treated with surgical debulking followed by radiation and chemotherapy. However, radioresistant tumors such as osteogenic sarcoma with a mass effect to the brain are usually best treated with radical surgical resection and chemotherapy.⁴⁶ With the recent advancement in chemotherapy, prognoses of these tumors are improving. A five-year survival rate from nasopharyngeal carcinomas is reported at 35% to 70%,²⁸ and for the rhabdomyosarcomas, a three-year survival rate is reported at approximately 80% to 90%.⁴⁷

Conclusions

    The management of skull base tumors continues to evolve as techniques continue to be developed. Up-to-date knowledge on tumor biology, treatment modality and effect, and a well-controlled, long-term outcome study should be carefully followed. Currently, tumors should be managed according to their biologic aggressiveness, the extent and location of the tumor, and the patient’s clinical presentation.

    Appreciation is expressed to Jennifer Pryll for her illustrative and photographic assistance and to Joseph Reister for editing and preparing the manuscript.

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From The George Washington University Medical Center; Washington, DC 20037.

Address reprint requests to Laligam N. Sekhar, MD, Department of Neurological Surgery, The George Washington University Medical Center; 2150 Pennsylvania Ave NW, Ste 7-420, Washington, DC 20037.

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