The Skull Base, Paranasal Sinuses, and Related Malignancies Chad A. Zender, MD and Guy J. Petruzzelli, MD*

Address *Department of Otolaryngology–Head and Neck Surgery, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. E-mail: [email protected] Current Oncology Reports 2003, 5:147–151 Current Science Inc. ISSN 1523-3790 Copyright © 2003 by Current Science Inc.

Tumors of the anterior skull base most commonly originate from the nasal cavity and paranasal sinuses. Such early presenting signs and symptoms as nasal obstruction, epiphora, and epistaxis are frequently thought to have a benign pathology. Proptosis, vision changes, skin fixation, and cervical adenopathy are associated with advanced disease. Treatment of paranasal sinus tumors is complex, involving combined therapy and multidisciplinary teams. The particular method of treatment is determined by multiple factors, including tumor histopathology, age, health of the patient, and extent of disease. In the past several years, numerous approaches to the skull base have evolved, allowing otolaryngologists and head and neck surgeons to extend earlier operative indications and treat cancers that were previously deemed unresectable. This article reviews some of the current surgical and nonsurgical approaches to skull base tumors originating from the paranasal sinuses.

Introduction Malignant tumors of the paranasal sinuses arise from the multiple histologic cell types (salivary gland, epithelial, connective tissue, and neural) on the sinonasal tract [1••]. The rarity of these tumors and their often-silent course make early diagnosis extremely difficult [2]. Consequently, patients with these tumors often present at an advanced stage, and extensive transcranial skull base procedures with adjuvant radiotherapy and neoadjuvant or adjuvant chemotherapy are often necessary. Comprehensive staging information is needed before therapy can be initiated. A histopathologic diagnosis, imaging studies, and the patient’s current physical status must be assessed. At our institution, prior to initiating therapy, we present cases at a multidisciplinary treatment planning conference. At the conference, physical examination findings, pathology results, and imaging studies are discussed among head and neck surgeons, medical

oncologists, radiation oncologists, and representatives of a variety of other disciplines to arrive at a comprehensive treatment plan for the patient.

Paranasal Sinuses An understanding of the anatomy of the paranasal sinuses is critical for accurate assessment of local tumor extension and relationships to critical structures. Presenting symptoms reflect the location in which the tumor arises and the penetration of the tumor into related skull base structures such as the orbit, anterior, or central skull base. Variability in the degree of pneumatization of the paranasal sinuses increases the number of potential sites in which these tumors develop. For example, the ethmoid sinuses can have anywhere from seven to 14 cells per side [3]. Because of this large degree of variation, the anatomy must be well understood. The maxillary sinus is the first of the four pairs of sinuses to develop around the 65th day of gestation [4]. The maxillary sinus and the ethmoid sinus are both present at birth. The superior portion of the maxillary sinus forms the floor of the orbit, its medial aspect forms part of the lateral nasal wall, and the posterior portion forms the anterior border of the pterygopalatine fossa/infratemporal fossa and the central skull base. The size of the maxillary sinus should also be considered. It is the largest of the sinuses, measuring approximately 34 × 33 × 23 mm and with a capacity of about 14.75 mL [5]. This large size allows tumors to grow considerably before symptoms arise and accounts for the fact that the maxillary sinus is the most common site of paranasal sinus and skull base tumors. Tumors of the maxilla often cause symptoms that mimic benign processes like sinusitis, making early diagnosis difficult. The location of the infraorbital nerve is another consideration. It lies along the orbital floor just above the roof of the maxillary sinus. Its location becomes particularly significant with such tumors as adenoid cystic carcinoma, which is noted for perineural invasion. The American Joint Committee on Cancer (AJCC) staging criteria for maxillary sinus tumors are outlined in Table 1. The location of the ethmoid sinus allows extension of tumors to the anterior skull base and orbit with relative ease. The lateral aspect of this sinus includes the lamina papyracea or “paper-thin” bone that makes up a portion of the medial aspect of the orbit. The fragility of this bone

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Table 1. Maxillary sinus tumor criteria T1 T2 T3

T4

Tumor limited to the antral mucosa with no bony erosion or destruction Tumor with bony erosion or destruction into the hard palate or medial antral wall Tumor that invades any of the following: subcutaneous tissues or skin of cheek, posterior wall of antrum, floor or medial of the orbit, ethmoid sinuses, or pterygoid plates Tumor that invades orbital contents beyond the floor or medial wall or the cribriform plate, frontal or sphenoid sinus, nasopharynx, or base of skull

Adapted from AJCC [20].

allows tumor extension into the orbit, resulting in proptosis, diplopia, and other ocular symptoms. The roof of the ethmoid sinus is the only barrier between this sinus and the anterior cranial fossa. The lateral lamella is the thinnest portion of this bone and allows a path of least resistance for tumor extension into the skull base and anterior cranial fossa. The cribiform plate is part of the ethmoid bone and is also close to the ethmoid sinuses. Its location allows for alterations in smell and taste to arise with invading tumors. The AJCC staging for ethmoid sinus cancer is outlined in Table 2. The frontal sinus has the lowest frequency of primary malignancy (the maxilla is the most frequent) [6•]. Its location is in an area that allows direct extension into the anterior cranial fossa. The supraorbital nerve is just above the supraorbital rim and is also at risk for perineural extension intracranially. The sphenoid sinus is the last of the paranasal sinuses. It too has a large degree of variation and is in close proximity to many vital structures. The carotid artery, the optic nerve, and the vidian nerve are all in close relationship to this sinus. The location of this sinus within the skull makes it extremely difficult to completely excise tumors en bloc, often necessitating combined-modality therapy for malignancies in this location.

Malignant Skull Base Tumors Malignant skull base tumors represent a subset of malignant tumors of the paranasal sinuses. By virtue of their location, advanced paranasal tumors may require a limited craniotomy or craniectomy to obtain an oncologic margin or cranial exposure to obtain distal control of the internal carotid artery. Etiologic factors related to malignant paranasal sinus tumors may include industrial fumes, wood dust, and heavy metals such as nickel or cadmium [6•]. Malignant paranasal sinus tumors account for 3% of all head and neck cancers. Fortunately, less than half of these tumors can be considered skull base malignancies. These tumors can be classified as benign or malignant, epithelial or nonepithelial, and primary

or metastatic. This article reviews some of the important characteristics of the most common malignancies in this area, including squamous cell carcinoma, adenocarcinoma, olfactory neuroblastoma, and adenoid cystic carcinoma. Melanomas and sinonasal undifferentiated carcinoma are also mentioned briefly. Benign tumors of the skull base and paranasal sinuses such as meningiomas, mesenchymal tumors, angiofibromas, and paragangliomas are not discussed. Squamous cell carcinoma is the most common sinonasal tumor [7]. In this location it is locally destructive and also has a propensity for regional metastasis. Squamous cell carcinoma of the paranasal sinus is most commonly seen in male patients and often presents in the fifth and sixth decades of life [8••]. Treatment for squamous cell carcinoma in this location is primary surgical resection. These tumors are radiosensitive, and radiotherapy has a role as either adjuvant or primary therapy along with chemotherapy in unresectable patients. Adenocarcinoma is the second most common tumor of the paranasal sinuses. It most frequently involves the ethmoid sinuses and has a classic relationship with dust exposure [9]. These tumors make up approximately 4% to 8% of all paranasal sinus tumors [10]. They are traditionally classified as low- or high-grade. Low-grade tumors are more likely to recur locally, whereas high-grade malignancies have a higher frequency of metastasis. Distant metastasis has been reported in approximately one third of high-grade tumors of this type [8••]. Twenty-percent of adenoid cystic carcinoma is found in the sinuses [10]. Because of its predilection for perineural and submucosal spread, adenoid cystic carcinoma is often quite advanced at the time of diagnosis. Intradural spread is seen in as many as one third of presenting patients [11]. Perineural spread is often associated with skip lesions, which make it difficult to obtain negative surgical margins. As for all of these tumors, the relationship of the sinuses to vital structures is another factor that makes it a challenge to obtain tumor-free margins. Melanoma is a rare tumor of the sinuses, but when it arises it is extremely aggressive, with very dismal 5-year survival. These tumors frequently present with black nasal drainage or discharge. Wide local excision with or without radiation is the treatment of choice. A meta-analysis by Brandwein et al. [12] shows that, unlike melanoma of the skin, local recurrence is the most common cause of failure with these tumors in the sinuses. Sinonasal undifferentiated carcinoma is a recently defined entity. This tumor is very poorly differentiated and typically presents with extensive sinus involvement. The prognosis is poor, and the treatment involves surgery, chemotherapy, and radiation. Olfactory neuroblastoma is a malignant tumor of the anterior cranial base derived from the mitotically active mitral cells of the olfactory tract. First described in the early 1900s, this rare tumor has traditionally been treated with

The Skull Base, Paranasal Sinuses, and Related Malignancies • Zender and Petruzzelli

Table 2. Ethmoid sinus tumor criteria T1 T2 T3 T4

Tumor confined to the ethmoids, with or without bony erosion Tumor extending into the nasal cavity Tumor extending into the anterior orbit, maxillary sinus, or both Tumor with intracranial and orbital extension including apex, involving sphenoid or frontal sinus and skin of nose

Adapted from AJCC [20].

surgery and postoperative radiotherapy. Primary surgical treatment of olfactory neuroblastoma should consist of craniofacial resection of the anterior fossa, dura, olfactory bulbs, and tracts. Levine et al. [13] at the University of Virginia have advocated definitive sequential chemotherapy and radiation followed by salvage craniofacial resection. Although several groups have developed anatomic staging systems for this tumor, no consensus has been reached. Interestingly, with the application of craniofacial surgery, survival of patients with this tumor has increased, and the incidence of cervical node metastasis approaches 15%.

Surgical Treatment Several factors have contributed to the feasibility of safe surgical treatment of skull base tumors, including transcranial tumors. Advances in diagnostic imaging have been most important in this regard. Magnetic resonance imaging (MRI) and CT scanning have allowed surgeons to approach tumors involving almost any site in the skull base. These imaging modalities render significant amounts of information about the relationships of these tumors to surrounding structures or the presence of cervical lymph node metastasis. The CT scan has the ability to show bony detail and lymph node involvement, whereas the MRI is superior in evaluating lesions that involve soft tissue such as the dura or brain. Because of the location of these tumors, both techniques are necessary to provide the complementary information required for accurate surgical planning. Prior to the advent of skull base surgery, paranasal sinus tumors with skull base extension were uniformly fatal. With recent advances in skull base surgical techniques, survival rates range from 39% to 86% [14••]. Various approaches to tumors of the paranasal sinuses have been established. The type of approach depends on the extent of disease, histopathology, and expertise of the treatment team. This consideration is significant because recurrence is the cause of death in the majority of patients. Only 5% to 10% of patients with these tumors die of distant metastasis, which explains why most authorities believe that chest radiography and liver function tests are adequate for an initial metastatic workup.

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Histopathology is a critical factor in selection of the appropriate surgical technique. A definitive histopathologic analysis, including immunohistologic staining, if necessary, must be obtained preoperatively. Sinonasal endoscopy with intraoperative surgical navigation has proven to be very useful because it provides biopsy material with minimal disruption of adjacent tissues and little patient morbidity. Tumors with more extensive involvement in the skull base or deep sinuses may require an extensive resection. Anterior craniofacial procedures that have both extracranial and intracranial (intra- or extradural) components are often used for larger tumors. These technically advanced procedures are often assisted by stereotactic guidance systems. These systems use CT or MRI interface with computers to give real-time imaging, so that vital structures can be avoided and clear surgical margins can be obtained. Enhancements in imaging technology and intraoperative navigational systems have also helped to expand the application of endoscopic surgery from biopsy to definitive resection of skull base tumors. Contraindications for surgery include involvement of the cavernous sinuses with cranial nerve palsies or deep invasion of the pterygoid space, often signs of inoperability [8••]. The physical status of the patient is also considered. Although the frequency of tumors in this area remains small, our ability to treat them continues to grow. With the expansion of endoscopic, laser, and minimally invasive surgery, recovery time and cosmetic deformity are decreasing and functionality is maintained.

Nonsurgical Treatment The two main nonsurgical therapeutic modalities for paranasal sinus and skull base tumors are radiotherapy and chemotherapy, or a combination of the two. These modalities can be used as a primary treatment for advanced lesions that are considered to be inoperable. At our institution, the preferred method is primary surgery with adjuvant radiotherapy. Primary nonsurgical therapy is composed of concurrent chemotherapy (weekly platinumor taxane-based regimen) with standard-fraction radiotherapy and surgical salvage. Our experience correlates with the 36% to 86% survival rates seen in skull base neoplasms reported from other institutions. Radiotherapy enhanced with three-dimensional imaging has significantly improved our ability to treat tumors of the skull base and paranasal sinus region. Radiation therapists are now able to irradiate tumors that are within millimeters of such vital structures as the optic nerve. These techniques range from fractionated radiation over a 6-week time period to radiosurgery that delivers a one-time pulse dose of 10 to 20 Gy directly to the tumor. Castro et al. [15] report a 58% to 85% 5-year survival rate with select tumors of the skull base using these techniques, and Parsons et al. [16] report locoregional control rates ranging from 30% to 100%.

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As with any form of radiation, the side effects, both acute and chronic, limit the dose that can be administered. Another problem with radiotherapy is that it can be used only once (although sometimes boost doses can be given) because its toxicity is cumulative. Finally, even with these advances in stereotactics, tumors of the central skull base and petroclival region can be difficult to isolate without significant irradiation to local structures. Because tumors of the skull base are rare, large studies with chemotherapy have not been performed, and most of the data are extrapolated from reports concerning tumors of the oral cavity and pharynx. Chemotherapy is not typically used as a single primary modality for treatment of cancers in the head and neck. Current data support concomitant chemotherapy and radiation for oral cavity and oropharyngeal cancer rather than radiation alone [17•]. The data for cancers of the skull base are limited, but Choi et al. [18] report response rates as high as 94% and a 5-year survival rate of 54% with combined chemotherapy and radiation. Anatomic considerations become important with a new method of delivery, such as intra-arterial chemotherapy. Nishino [19] retrospectively reviewed data from patients with maxillary sinus cancer who received multimodality therapy including conservative surgery, radiation, and intra-arterial (internal maxillary) chemotherapy. These data showed survival rates of 77% at 5 years.

Our Data We recently reviewed our institutional experience with malignant tumors of the paranasal sinuses and anterior cranial base. Since 1994, the senior author at the Loyola University Medical Center in Mayview, IL has treated 98 patients with malignant tumors of the paranasal sinuses, including 40 women and 58 men, with ages ranging from 10 to 80 years. Thirty-six of the 98 patients had tumors extending beyond the paranasal sinuses that required combined intracranial and extracranial (ie, skull base) resection. Twenty-five of the 36 patients had tumors of the central compartment of the anterior skull base and were treated with conventional craniofacial resection. In this group, 10 patients had olfactory neuroblastoma, six had squamous cell carcinoma, three had sinonasal undifferentiated carcinoma, and two each had chondrosarcoma, neuroendocrine carcinoma, and melanoma. The remaining 11 patients had primary tumors of the maxilla with extension to the central skull base and cavernous sinus. These tumors were resected via an anterolateral cranial base, requiring orbital exenteration in three patients. Of these 11 patients, seven had adenoid cystic carcinoma, three had adenocarcinoma, and one had a basaloid squamous cell carcinoma. Patients with transcranial tumor or dural margins that were positive for tumor were treated with adjuvant concurrent chemotherapy and radiation. In our experience, the overall mean survival for patients with malignant skull base

tumors is 30 months. Positive dural margins and aggressive histologies (melanoma and undifferentiated carcinoma) are associated with a poorer overall prognosis.

Conclusions Tumors of the skull base and paranasal sinuses are complex clinical entities. An intimate understanding of the anatomy of the skull base is crucial in treatment planning. An understanding of the variability in the pathogenesis of different tumors in this region is also important for successful treatment of cancers of the sinuses. For these reasons patients should be treated by a team of specialists including head and neck surgeons, neurosurgeons, radiation oncologists, and medical oncologists. Surgery remains the primary therapy at our institution, but with advances in chemotherapy and radiation, the role of these modalities has increased. With the recent advances in skull base therapy, we are now able to give people who were previously without hope a chance at survival.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.•• Osguthorpe, JD, Patel S: Cranio-facial approaches to tumors of the anterior skull base. Otolaryngol Clin North Am 2001, 34:1123–1142. This text gives a great overview of anatomy, pathology, and surgical approaches to primary tumors of the skull base. 2. Batsakis JG, ed: Tumors of the Head and Neck, edn 2. Baltimore: Williams & Wilkins; 1979. 3. Van Alyea OE: Ethmoid labyrinth: anatomic study, with consideration of the clinical significance of its structural characteristics. Arch Otolaryngol 1939, 29:881–902. 4. Libsera C, Laude M, Libsera JC: The pneumatization of the accessory cavities of the nasal fossae during growth. Anat Clin 1981, 2:265–278. 5. Ritter FN: The Paranasal Sinuses, edn 2. St. Louis: Mosby; 1978. 6.• Keane WM, Atkins JP Jr, Wetmore R, Vidas M: Epidemiology of the head and neck cancer. Laryngoscope 1981, 91:2037–2045. A nice reference on the frequency of tumors of the paranasal sinuses and other tumors of the head and neck. 7. Bridger MWM, Beale FA, Bryce DP: Carcinoma of the paranasal sinuses: a review of 158 cases. J Otolaryngol 1978, 7:379–388. 8.•• Bailey BJ, Calhoun KH, eds: Head and Neck Surgery—Otolaryngology, edn 3. Philadelphia: Lippincott Williams & Wilkins; 2001. A standard otolaryngology text that was recently revised. It includes a helpful summary of the anatomy and pathology of the paranasal sinuses. 9. Klintenberg C, Olofsson J, Hellquist H, Sokjer H: Adenocarcinoma of the ethmoid sinuses, Cancer 1984, 54:482–488. 10. Goepfert H, Luna MA, Lindberg RD, White AK: Malignant salivary gland tumors of the paranasal sinuses and nasal cavity. Arch Otolaryngol 1983, 109:662–668. 11. Pitman K, Prokopakis E, Aydogan B, et al.: The role of skull base surgery for the treatment of adenoid cystic carcinoma of the sinonasal tract. Head Neck 1999, 21:402–407. 12. Brandwein MS, Rothstein A, Lawson W, et al. Sinonasal melanoma: a clinicopathologic study of 25 cases and literature meta-analysis. Arch Otolaryngol Head Neck Surg 1997, 123:290–296.

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13.

Levine PA, Gallagher R, Cantrell RW: Esthesioneuroblastoma: reflections of a 21-year experience. Laryngoscope 1999, 109:1529-1543. 14.•• Cummings CW, Frederickson JM, Harker LA et al., eds: Otolaryngology Head and Neck Surgery, edn 3. St. Louis: Mosby; 1998. This standard otolaryngology textbook gives a broad yet in-depth look at the paranasal sinuses and the anterior skull base. 15. Castro JR, Linstadt DF, Bahary JP, et al.: Experience in charged particle irradiation of tumors of the skill base. Int J Radiat Oncol Biol Phys 1994, 29:647–655. 16. Parsons JT, Mendenhall WM, Mancuso AA, et al.: Malignant tumors of the nasal cavity and ethmoid and sphemoid sinuses. Int J Radiat Oncol Biol Phys 1988, 14:11–22. 17.• Brizel DM, Albers ME, Fisher SR, et al.: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998, 338:1798-1804. This study is very important with respect to nonsurgical treatment modalities for head and neck cancer.

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