39

Nasal Cavity and Paranasal Sinuses

Anatomy

Nasal Vestibule

The nasal vestibule is the triangular-shaped space located inside the aperture of the nostril as a slight dilatation that extends as a small recess toward the apex of the nose. It is defined laterally by the alae, medially by the membranous septum, the distal end of the cartilaginous septum and columella, and inferiorly by the adjacent floor of the nasal cavity. It is lined by skin containing hairs and sebaceous glands; therefore, tumors at this location are those that frequently arise from the skin, usually squamous cell cancers (23) but may occasionally be basal cell carcinoma (43), sebaceous carcinoma (50), melanoma (57), non-Hodgkin's lymphoma (66).

Nasal Cavity

The nasal cavity extends from the hard palate inferiorly to the base of skull superiorly. It is above and behind the vestibule and is defined anteriorly by the transition from skin to mucous membrane and posteriorly by the choanae, which open directly into the nasopharynx (12). The lateral walls correspond with the medial walls of the maxillary sinuses and consist of thin bony structures that have three shell-shaped projections (superior, middle, and inferior conchae or turbinates) into the nasal cavity. The septum divides the nasal cavity into right and left halves.
Each nasal cavity contains an olfactory region, consisting of the superior nasal concha and the opposed part of the septum, and a respiratory region, which comprises the rest of the cavity. Within the olfactory region, the olfactory nerves from the superior nasal concha and the upper third of the septum penetrate the roof of the nasal cavity and exit through the cribriform plate. The respiratory region comprises the remaining part of the nasal cavity and contains orifices connecting the nasal cavity with the paranasal sinuses. The superior meatus connects the nasal cavity with the posterior ethmoid cells, the middle meatus with the anterior and middle ethmoid cells and the frontal and maxillary sinuses, and the inferior meatus with the nasolacrimal duct. The sphenoid sinus drains into the nasal cavity through an opening in the anterior wall.

Ethmoid Sinuses

The ethmoid sinuses are composed of several small cavities, the ethmoid air cells, within the ethmoid labyrinth located below the anterior cranial fossa and between the nasal cavity and the orbit. They are separated from the orbital cavity by a thin, porous bone, the lamina papyracea, and from the anterior cranial fossa by a portion of the frontal bone, the fovea ethmoidalis. They are in close proximity to the optic nerves laterally and the optic chiasm posteriorly. The ethmoid sinuses are divided into anterior, middle, and posterior groups of air cells. The middle ethmoid cells open directly into the middle meatus. The anterior cells may drain indirectly into the middle meatus via the infundibulum. The posterior cells open directly into the superior meatus.

Maxillary Sinuses

The maxillary sinuses are the largest of the paranasal sinuses. They are pyramid-shaped cavities located in the maxillae. The lateral walls of the nasal cavity form the base and the roofs correspond to the orbital floors, which contain the infraorbital canals. The floors of the maxillary sinuses are composed of the alveolar processes. The apices extend toward and frequently into the zygomatic bones. Secretions drain by mucociliary action into the middle meatus via the hiatus semilunaris through an aperture near the roof of the maxillary sinus. Ohngren's line is a theoretic plane dividing each maxillary sinus into the suprastructure and infrastructure; it is defined by connecting the medial canthus with the angle of the man-dible.

Sphenoid Sinus and Frontal Sinuses

The sphenoid bone forms a midline inner cavity that communicates with the nasal cavity through
an aperture in its anterior wall. It is directly apposed superiorly to the pituitary gland and optic chiasm, laterally to the cavernous sinuses, anteriorly to the ethmoid sinuses and nasal cavity, and inferiorly to the nasopharynx. The paired, typically asymmetric frontal sinuses are located between the inner and outer tables of the frontal bone. They are anterior to the anterior cranial fossa, superior to the sphenoid and ethmoid sinuses, and superomedial to the orbits. They usually communicate with the middle meatus of the nasal cavity.

Epidemiology

Cancers of the nasal cavity and paranasal sinuses are relatively uncommon. Fewer than 4,500 patients are diagnosed with these neoplasms each year in the United States, an incidence of 0.75 per 100,000 (59). Cancers of the maxillary sinus are twice as frequent as those of the nasal cavity; cancers of the ethmoid, frontal, and sphenoid sinuses are extremely rare. They generally develop after the age of 40 years, except for esthesioneuroblastoma (ENB), which has a unique bimodal age distribution (20), and occur twice as frequently in men than in women (38). These tumors are more common in Japan and South Africa.

The etiologic factors vary by tumor type and location. Adenocarcinomas of the nasal cavity and ethmoid sinus have been reported to occur more frequently in carpenters and sawmill workers who are exposed to wood dust (1,2,32). Synthetic wood, binding agents, and glues may also be involved as cocarcinogens (61). Squamous cell carcinomas of the nasal cavity have been seen more often in nickel workers (67). Maxillary sinus carcinomas have been associated with radioactive thorium-containing contrast material (Thorotrast) used for radiographic study of the maxillary sinuses in the past. Occupational exposure in the production of chromium, mustard gas, isopropyl alcohol, and radium also may increase the risk for sinonasal carcinomas.
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Cigarette smoking is reported to increase the risk of nasal cancer, with a doubling of risk among heavy or long-term smokers and a reduction in risk after long-term cessation. After adjustment for smoking, a significant dose-response relation has also been noted between alcohol drinking and risk of nasal cancer (72).

Natural History

Nasal Vestibule

Nasal vestibule carcinomas can spread by direct invasion of the upper lip, gingivolabial sulcus, premaxilla (early events), or nasal cavity (late event) as shown in Figure 39.1. Vertical invasion may result in septal (membranous or cartilaginous) perforation or alar cartilage destruction. Lymphatic spread from nasal vestibule carcinomas is usually to the ipsilateral facial (buccinator and mandibular) and submandibular nodes. Large lesions extending across midline may spread to the contralateral facial or submandibular nodes. The incidence of nodal metastasis at diagnosis is approximately 5% (6,45,70). Without elective nodal treatment, approximately 15% of patients
develop nodal relapse. Hematogenous metastases are rare.

Nasal Cavity and Ethmoid Sinuses

The pattern of contiguous spread of carcinomas varies with the location of the primary lesion. Tumors arising in the upper nasal cavity and ethmoid cells can extend to the orbit through the thin lamina papyracea and to the anterior cranial fossa via the cribriform plate, or they may grow through the nasal bone to the subcutaneous tissue and skin. Lateral wall primaries invade the maxillary antrum, ethmoid cells, orbit, pterygopalatine fossa, and nasopharynx. Primaries of the floor and lower septum may invade the palate and maxillary antrum. Perineural extension (typically involving branches of the trigeminal nerve) is seen most frequently with adenoid cystic carcinomas.

Lymphatic spread of nasal cavity primaries is uncommon, although spread to retropharyngeal and cervical lymph nodes is possible. In The University of Texas M. D. Anderson Cancer Center (MDACC) series of 51 patients, only 1 had palpable subdigastric nodes at diagnosis. Of the 36 patients who did not receive elective lymphatic irradiation, 2 (6%) experienced subdigastric nodal relapse (4). Hematogenous dissemination is rare. In the MDACC series, for example, distant metastasis to bone, brain, or liver occurred in 4 of 51 patients (4).

The olfactory region is the site of origin of ENB and, occasionally, adenocarcinomas.

Esthesioneuroblastoma is a tumor of neural crest origin first reported by Berger and Luc in 1924 as esthesioneuroepithelioma olfactif (7). Other names include olfactory neuroblastoma and esthesioneurocytoma. Esthesioneuroblastoma constitutes approximately only 3% of all intranasal neoplasms. About 250 cases were reported in the literature between 1924 and 1990 (24). The tumor typically is composed of round, oval, or fusiform cells containing neurofibrils with pseudorosette formation and diffusely increased microvascularity (30). Esthesioneuroblastoma may be mistaken for any other “small round-cell tumor,” that is, a group of aggressive malignant tumors composed of small and monotonous undifferentiated cells that includes Ewing's sarcoma, peripheral primitive neuroectodermal tumor (also known as extraskeletal Ewing's), rhabdomyosarcoma, lymphoma, small cell carcinoma (undifferentiated or neuroendocrine), and mesenchymal chondrosarcoma. The clinical presentations of these entities often overlap, but clinicopathologic features and immunohistochemistry may help in differentiation.

The route of contiguous spread of ENBs is similar to that of ethmoid carcinomas. Lymph node involvement and distant metastasis are infrequent at diagnosis (11% and 1%, respectively [8]).

Maxillary Sinuses

The pattern of spread of maxillary sinus cancers varies with the site of origin. Suprastructure tumors extend into the nasal cavity, ethmoid cells, orbit, pterygopalatine fossa, infratemporal fossa, and base of skull (Fig. 39.2, A through C). Invasion of these structures gives lesions of the suprastructure a poorer prognosis. As well, treatment is associated with greater morbidity as a consequence of craniofacial resection or radiation of intracranial and ocular structures. Infrastructure tumors often infiltrate the palate, alveolar process, gingivobuccal sulcus, soft tissue of the cheek, nasal cavity, masseter muscle, pterygopalatine space, and pterygoid fossa (Fig. 39.2, D through J).

The maxillary sinuses are believed to have a limited lymphatic supply (60), and there is a correspondingly low incidence of lymphadenopathy at diagnosis (37,55). Only 6 of the 73 patients (8%) in the MDACC series had palpable lymphadenopathy at diagnosis. The incidence of nodal spread, however, varies with the histologic type (17%, or 5/29, for patients with
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squamous cell and poorly differentiated carcinomas versus 4%, or 1/27, for patients with adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma). The incidence of subclinical disease as reflected in the rate of nodal relapse in patients who did not receive elective neck treatment also varies with histologic type (38%, or 9/24, for patients with squamous cell and poorly differentiated carcinomas versus 8%, or 2/26, for patients with adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma). The cumulative incidence of nodal involvement (gross and microscopic) for patients with squamous cell and poorly differentiated carcinomas is about 30%. The risk of regional recurrence after treatment is 20% to 30% or higher, depending on the extent of disease and elective neck treatment (46). Ipsilateral subdigastric and submandibular nodes are involved most frequently. Hematogenous spread is uncommon.

Clinical Presentation

Nasal Vestibule

Carcinomas of the nasal vestibule usually present as asymptomatic plaques or nodules, often with crusting and scabbing. Advanced lesions may extend beyond the vestibule and may cause pain, bleeding, or ulceration. Large ulcerated lesions may become infected, leading to severe tenderness that requires anesthesia for complete clinical assessment.

Nasal Cavity

Nasal cavity tumors present with symptoms and signs of nasal polyps (e.g., chronic unilateral discharge, ulcer, obstruction, anterior headache, and intermittent epistaxis), hence delaying the diagnosis. Additional symptoms and signs develop as the lesion enlarges: medial orbital mass, proptosis, expansion of the nasal bridge, diplopia resulting from invasion of the orbit, epiphora due to obstruction of the nasolacrimal duct, anomaly of smell or anosmia from involvement of the olfactory region, or frontal headache due to extension through the cribriform plate.

The common presenting symptoms of ENBs are nasal obstruction and epistaxis. Spaulding et al. (64) found that anosmia could precede diagnosis by many years. Other symptoms are related to contiguous disease extension into the orbit (proptosis, visual-field defects, orbital pain, epiphora), paranasal sinuses (medial canthus mass, facial swelling), anterior cranial fossa (headache), or are due to inappropriate antidiuretic hormone secretion (64).

Ethmoid Sinuses

The presenting symptoms and signs are central/facial head-aches and referred pain to the nasal or retrobulbar region, a subcutaneous mass at the inner canthus, nasal obstruction and discharge, diplopia, and proptosis. Of the 34 patients with ethmoid sinus cancers treated at MDACC between 1969 and 1993, nasal cavity symptoms (nasal obstruction, epistaxis, discharge)
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were reported in 25 patients (74%), orbital symptoms (diplopia, orbital pain, vision loss, proptosis, inner canthus mass, tearing) in 12 (35%), headache in 6 (18%), and hyposmia or anosmia in 5 (15%) (28).

Maxillary Sinuses

Maxillary sinus cancers usually are diagnosed at advanced stages. Symptoms and signs are facial swelling, pain, or paresthesia of the cheek induced by disease extension to the premaxillary region, epistaxis, nasal discharge and obstruction related to tumor spread to the nasal cavity, ill-fitting denture, alveolar or palatal mass, unhealed tooth socket after extraction from spread to the oral cavity, and proptosis, diplopia, impaired vision, or orbital pain due to orbital invasion (27).

Diagnostic Work-Up

The recommended pretreatment physical, diagnostic, and staging evaluations are listed in Table 39.1.

Physical Examination

Inspection and palpation of the orbits, nasal and oral cavities, and nasopharynx provide preliminary determination of tumor extent. Bimanual palpation is important in assessing contiguous extension of nasal vestibule lesions and in identifying buccinator and submandibular nodal involvement. Careful examination of cranial nerves is required. Fiberoptic nasal endoscopy after mucosal decongestion and topical analgesia allows assessment of local extent and facilitates biopsy of tumor involving the nasal cavity or nasopharynx.

Radiographic Evaluation

Imaging plays a crucial role in the staging of sinonasal tumors. Magnetic resonance imaging (MRI) and computed tomography (CT) (33) scans are complementary. MRI is superior at detecting direct intracranial or perineural or leptomeningeal spread (62). T2-weighted MRI can be helpful in differentiating tumor (low signal) from obstructed secretions (bright) (63). CT is superior for detecting early cortical bone erosion or extension through the cribriform plate or orbital walls.

Certain features provide clues as to the nature of the tumors in this region. Slowly progressive lesions tend to deform instead of destroy bony structures. Intermediate-grade tumors can cause sclerosis of adjacent bone. Lymphomas tend to permeate bone without frank destruction, and carcinomas and sarcomas infiltrate and destroy adjacent bone.

Biopsy

Transnasal biopsy is preferred for tumors arising from or extending into the nasal cavity or nasopharynx. Some paranasal sinus tumors may be more easily sampled using transoral procedures or an open Caldwell-Luc approach.

Laboratory Studies

Complete blood counts and serum chemistries provide screening for distant metastases. Abnormalities of these tests can be further investigated as necessary.

Staging

The 6th edition of the American Joint Committee on Cancer (AJCC) TNM classification includes staging for cancers of the maxillary sinus, ethmoid sinus, and the nasal cavity (25). Significant updates in the 6th edition are:
· The nasoethmoid complex is divided into two regions: the nasal cavity proper and the ethmoid sinuses.
· The nasal cavity is divided into four subsites (vestibule, septum, floor, and lateral wall) and the ethmoid sinuses into two subsites (right and left).
· Descriptions of the T staging of ethmoid tumors was added.
· T4 maxillary sinus tumors are divided into T4a (resectable) and T4b (unresectable).
There was no official AJCC staging for nasal carcinomas before the publication of the 6th edition of the AJCC Cancer Staging Manual (25). Table 39.2 summarizes the University of Florida (UF) nasal tumor staging system (54) and the Kadish staging system for ENB (34) used in the past. Tumors of the sphenoid and frontal sinuses are rare, and no specific staging system is available.

Pathologic Classification

Most nasal vestibule cancers are squamous cell carcinomas; the remaining are basal cell or adnexal carcinomas. The majority of cancers of the nasal cavity and paranasal sinuses are also squamous cell carcinomas, although minor salivary gland neoplasms (adenocarcinoma, adenoid cystic carcinoma, and
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mucoepidermoid carcinoma) account for 10% to 15% of lesions in these locations. Melanoma accounts for 5% to 10% of nasal cavity malignancies but is rare in the paranasal sinuses. Neuroendocrine carcinomas of the sinonasal region (including small cell carcinoma, ENB, and sinonasal undifferentiated carcinoma), lymphomas, sarcomas, and plasmacytomas are even less common.

Prognostic Factors

Patient-specific factors (primarily prognostic for survival) include age and performance status. Disease-specific factors (primarily prognostic for locoregional control) include location, histology, and locoregional extent (reflected in TNM stage), and perineural invasion. Extensive local disease involving the nasopharynx, base of skull, or cavernous sinuses markedly increases surgical morbidity as well as the risk of subtotal surgical excision. Tumor extension into the orbit may require enucleation but minimal invasion of the floor or medial wall may be dealt with by resection and reconstruction, sparing the globe.

General Management

Nasal Vestibule

Primary radiotherapy may be preferable for nasal vestibule carcinoma for better cosmetic outcome, although surgery can yield a high control rate with excellent cosmetic results in selected small superficial tumors. Depending on the location and size of the primary tumor, radiation treatment can be delivered by external-beam irradiation, brachytherapy, or a combination of both. Cartilage invasion is not a contraindication for radiation therapy because the risk for necrosis is low with fractionated treatment (48). Rare cases of large primary disease with extensive tissue destruction and distortion are best managed by surgical resection in combination with pre- or postoperative radiotherapy, although there are proponents of primary radiotherapy with salvage surgery in this situation (44). Experienced prosthodontists can design aesthetically satisfactory nasal prostheses after radical surgery.

Nasal Cavity and Ethmoid Sinuses

Radiotherapy and surgery are equally effective in curing early lesions of the respiratory region. The choice of therapy, therefore, depends on the size and location of the tumor and the anticipated cosmetic outcome. Posterior nasal septum lesions generally are treated by surgery, but small anterior-inferior septal lesions (≤1.5 cm) can be treated effectively with interstitial brachytherapy (192Ir implant). For cosmetic considerations, it is usually preferable to treat lateral wall lesions extending to the ala nasi with external irradiation. Locally advanced lesions of the respiratory region (stages II-IVa) are best treated with surgery, with or without postoperative irradiation.

A single modality treatment, either surgery or radiotherapy, yields >90% ultimate locoregional control for early ENBs (Kadish stage A) (20). The optimal therapy for stage B disease is unclear, partly because this group is heterogeneous; a combination of surgery and radiotherapy may have a slight advantage. For patients with stage C lesions, evidence suggests better results with the combination of surgery and radiotherapy. The available data do not justify routine elective nodal treatment because the incidence of isolated nodal relapse is <15%.

Ethmoid sinus carcinomas traditionally have been managed with surgery and postoperative radiotherapy. Selected cases may be treated with radiation alone or with radiotherapy and concurrent chemotherapy to avoid structural or functional deficits (69). Surgery generally involves medial maxillectomy and en bloc ethmoidectomy; a craniofacial approach is required if tumor extends superiorly to the ethmoid roof or olfactory region (11,41).

Maxillary Sinuses

Surgery alone can yield a high control rate in patients presenting with T1 or T2 tumors of the infrastructure. The combination of surgery and postoperative radiotherapy is the treatment of choice for patients with more advanced but resectable disease who are medically fit to undergo resection. Radical maxillectomy with or without orbital exenteration may be necessary, and a craniofacial approach is used if the tumor extends superiorly to the ethmoid roof or olfactory region. Definitive radiotherapy generally is recommended only for patients who are medically inoperable or who refuse radical surgery.

Chemotherapy—Neoadjuvant and Concomitant

Neoadjuvant chemotherapy is sometimes offered in order to reduce tumor volume, which may permit removal of tumor with a less morbid resection or facilitate radiotherapy planning if shrinkage pulls away tumor from critical structures such as brain, optic nerve, or chiasm. Alternatively, chemotherapy may be given concurrent with radiotherapy in the management of inoperable tumors on the basis of improved results in more frequent head and neck carcinomas. The sequence and agents used vary with the tumor type, tumor extent, and medical comorbidities. In general, the data suggest that concurrent chemotherapy is more effective than neoadjuvant chemotherapy with respect to local control.

Chemotherapy is not routinely for patients with ENB. Although responses to chemotherapy have been reported, they are usually of limited duration (68). Overall, local therapy with surgery and postoperative radiotherapy (58) yield excellent results at 5 years with regard to both overall survival (93.1%) and local control (96.2%). Concurrent chemotherapy during radiation may be considered in inoperable cases.

Palliation

Symptoms of incurable sinonasal cancer are particularly distressing. Multidisciplinary input is required even with very advanced cases as palliation may involve limited surgery, radiotherapy, chemotherapy, investigational studies, or best supportive care. The morbidity of each modality has to be balanced with the benefit to symptom control and improvement in quality of life. Attention is required to address in particular:
· the control of pain and discomfort as a first priority, and
· the impact of disfigurement and dysfunction, which is frequently present.

Chemotherapy may be given as single agent in investigational setting. If radiotherapy is given, larger dose per fraction is the usual practice in order to reduce the duration of treatment. However, if concurrent chemotherapy is added, consideration should be given to treating at 2 Gy per fraction to avoid severe acute effects. Treatment with radiotherapy or chemotherapy is often effective in reducing tumor bulk and providing relief of symptoms such as disfiguring masses, proptosis, discomfort or neuropathic pain, headache, epistaxis or other bleeding, nasal obstruction or discharge, and trismus.
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Radiation Therapy Techniques

Nasal Vestibule

Target Volumes

For small, well-differentiated lesions measuring ≤1.5 cm, small fields with a 1- to 2-cm margin are appropriate. The initial target volume for all poorly differentiated tumors and well-differentiated primaries of >1.5 cm without palpable lymphadenopathy includes both nasal vestibules with at least 2- to 3-cm margins around the primary tumor (wider margins for infiltrative tumor) as well as bilateral facial, submandibular, and subdigastric nodes. When lymph node involvement is present at diagnosis, the lower neck is also irradia-ted.

For postoperative radiotherapy, the initial target volume includes the operative bed plus a 1- to 1.5-cm margin and the elective nodal regions. The volume is reduced off the undissected nodal regions after 50 Gy (25 fractions) to deliver an additional 6 Gy to the surgical bed. At 56 Gy, a final cone down is done to include the preoperative tumor bed to administer 4 Gy for a total dose of 60 Gy. If there are positive margins or if only a limited excision was done, this final cone down is given 10 Gy (total dose, 66 Gy).

Treatment Techniques

External Beam

External-beam radiotherapy may be delivered using either superficial or orthovoltage x-rays for very thin lesions or electrons for thicker lesions. A technique for external-beam irradiation using electrons is illustrated in Figure 39.3. The patient lies supine, immobilized with the neck slightly flexed using a custom mask to align the anterior surface of the maxilla parallel with the top of the couch. This setup allows irradiation of the primary lesion through a vertical appositional field, usually with a combination of electrons and photons in a ratio of 4:1. Skin collimation is used to minimize scatter irradiation to the eye and reduce the penumbra of the beam and reduce the field size required. Custom beeswax bolus material (Fig. 39.3, D through F) is prepared to allow a relatively flat surface contour onto which the electron beam is incident, avoiding inhomogeneity due to oblique incidence and surface irregularity. Bolus is also used to fill the nares to avoid the dose perturbation due to the air cavity with electron beams. Bolus is removed for photon treatments for skin-sparing, unless there is involvement of the overlying skin. An intraoral Cerrobend-containing stent is used to displace the tongue posteriorly and partially shield the upper alveolar ridge.

When indicated, the right and left facial lymphatics are irradiated with appositional fields; these require an approximately
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15-degree gantry rotation to the respective side, each abutting the appositional primary lesion portal and the upper neck fields. The junctions are moved twice during the course of treatment to reduce dose heterogeneity. The submandibular and subdigastric nodes are treated with lateral parallel-opposed photon fields. In patients with involved nodes, these upper neck fields are matched inferiorly to an anterior portal treating the middle and lower neck nodes.

The external-beam radiation schedule for lesions up to 1.5 cm using a combination of electrons and photons is typically 50 Gy in 25 fractions followed by a boost of 10 to 16 Gy in 5 to 8 fractions (prescribed at 90% isodose line). Larger lesions to be treated by external-beam radiation alone receive 50 Gy in 25 fractions plus a boost of 16 to 20 Gy in 8 to 10 fractions. The schedule for elective nodal irradiation is 50 Gy in 25 fractions. Palpable nodes are given a boost to a total dose of 66 to 70 Gy in 33 to 35 fractions, depending on the size.

Brachytherapy

Brachytherapy for small lesions is accomplished using a 192Ir wire implant or, in selected cases, by intracavitary 192Ir mold. Hollow needles for afterloading are inserted under general anesthesia, which allows good exposure of the tumor as well as protection of the airway in the event of bleeding from the vascular Kiesselbach's plexus on the anterior nasal septum or from posterior hemorrhages originating from larger vessels near the sphenopalatine artery, behind the middle turbinate. Implantation of a T2 squamous cell carcinoma of the columella is shown in Figure 39.3. The recommended doses for low-dose-rate brachytherapy have evolved empirically and range from 60 to 65 Gy delivered during 5 to 7 days.

Brachytherapy may be used to replace an external-beam boost in patients with T1 or T2 nasal vestibule tumors following initial larger field radiotherapy. At 50 Gy, the patient is assessed and if there is good reduction of tumor volume, a boost of 20 to 25 Gy may be administered in about
2 days by low-dose-rate brachytherapy (Fig. 39.3, G through K).

High-dose-rate brachytherapy has also been used to deliver the boost. A custom mold of the nasal vestibule is fabricated and tumor is marked in the mold. Two to four plastic tubes with 1.0-cm spacing are inserted in the mold alongside the tumor. In the case of tumors of the lateral part of the vestibule, two catheters are placed on the inner aspect of the nasal vestibule. In the case of medially localized tumors, catheters are placed on both sides of the vestibule. Following external-beam radiotherapy to 50 Gy in 5 weeks, high-dose-rate brachytherapy is delivered in week 6. The dose is typically 3 Gy per fraction, given twice a day, to a total dose of 18 Gy specified at the center of the tumor. With a median overall treatment time (external-beam radiotherapy plus brachytherapy) of 36 days, this technique has been reported as yielding a 2-year local control of 86% and ultimate locoregional control of 100% (34).

Nasal Cavity and Ethmoid Sinuses

Target Volume

The technique for primary or postoperative external-beam radiotherapy of nasal cavity tumors depends on the depth of the neoplasm. For tumors located <3.5 to 4.0 cm from the skin of the apex of the nose, electrons may be used as 20 MeV electrons will provide coverage up to 5 cm in depth. A margin of at least 1 cm deep to the posterior edge has to be included in the full-dose volume. The technique is as previously described for nasal vestibule carcinoma. CT-based
treatment planning is necessary for accurate target localization and dose calcula-tion.

Intensity-modulated radiotherapy (IMRT) is recommended for tumors of the nasal cavity in which the target volume extends >5 cm depth or for tumors of the ethmoid sinus (Fig. 39.4). This technique delivers the desired dose to the target volume while minimizing the dose to critical organs such as cornea, lens, lacrimal glands, retina, optic nerve, optic chiasm, brain, and brainstem. For postoperative radiotherapy, the primary clinical target volume (CTV) descriptions are given in Table 39.3. The CTV1 consists of the primary tumor bed with a 1.0- to 1.5-cm margin. A boost subvolume consisting of high-risk regions (sites of positive margins, gross macroscopic residual tumor) to be treated to higher dose may be outlined. The CTV2 includes the entire operative bed. For ethmoid sinus tumors, this might include the frontal sinus, maxillary sinus, and sphenoid sinus. The bony orbit is part of the operative bed when orbital exenteration is performed because of tumor invasion. For lesions involving the ethmoid sinuses or olfactory region, the CTV should also include the cribriform plate. A third CTV may be delineated to encompass the tract of cranial nerve V2 to the foramen rotundum if there is perineural invasion. For primary radiotherapy using IMRT, the CTV1, consisting of the gross tumor volume plus a margin of 1 to 2 cm, receives the full dose of 66 to 70 Gy. In patients receiving neoadjuvant chemotherapy, target volume definition is based on the extent of disease before chemotherapy.

For three-dimensional (3D) conformal radiotherapy, the initial target volume for postoperative radiotherapy consists of the surgical bed with 1- or 2-cm margins, depending on the surgical pathology findings and the proximity of critical structures. The boost volume consists of areas at greatest risk for recurrence, such as close or positive resection margins or regions of perineural invasion, with 1- to 2-cm margins.

For small anteroinferior septal lesions, brachytherapy can be accomplished by a single-plane implant of the lesion with 2-cm margins. Elective neck irradiation is not given routinely even in patients with large tumors or ENB.

Setup and Field Arrangement

For target volumes <5 cm deep, an electron technique similar to that described for nasal vestibule carcinomas is used. Treatment devices include lead skin collimation to obtain a sharp penumbra as well as bolus material in the nasal cavity, postoperative defects, and on skin scars. An intraoral stent is used to depress the tongue, provide a patent airway, and aid in immobilization. Tungsten internal eye shields may be used if the target volume approaches the orbits (Fig. 39.3).

For 3D conformal or IMRT, the patient is immobilized in a supine position with the head positioned such that the hard palate is perpendicular to the treatment couch. Scars are marked with thin radio-opaque wires, bolus and other devices are positioned, and transverse CT images are obtained from the vertex to the upper mediastinum. For IMRT, rigid immobilization is necessary, including using special head and shoulder thermoplastic masks that extend down to the upper thorax. The shoulders may be additionally depressed and fixed, for example, using wrist straps tethered to a footboard. Target volumes are delineated as previously described.
For IMRT, multiple gantry angles are used based on beam-optimization algorithms. An example of a 10-field noncoplanar arrangement with two vertex beams is shown in Figure 39.4. The beam angle selections are based on the same principles as for 3D conformal therapy:
· Preference for the shortest path to the target;
· Avoidance of direct irradiation of the critical structures (e.g., avoid beam entry through the contralateral eye after ipsilateral exenteration); and
· Use of as large beam separation as possible.
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Inverse planning is usually done and multiple iterations may be necessary to ensure that the following are accomplished:
· Targets are covered;
· Normal tissue constraints are respected; and
· Dose is relatively homogenous.

Dose calculations should include heterogeneity corrections because of the significant amount of air and bone of the sinuses. The radiation oncologist must work closely with the physicist and dosimetrist. It is important to realize that the criteria for accepting or rejecting the plan may not be evident from the dose-volume histogram.

For 3D conformal radiotherapy, anterior oblique wedge-pair photon fields are appropriate for lesions located in the anterior lower half of the nasal cavity. Opposed-lateral fields may be used to treat tumors at the posterior part of the nasal fossa, provided the ethmoid cells are not involved. The optic pathway can be excluded from the radiation fields with this setup. For primaries of the upper nasal cavity and ethmoidal air cells, a three-field setup allows coverage of the ethmoid cells while sparing the optic apparatus. CT-based treatment planning is necessary to select beam and wedge angles (usually 45 to 60 degrees) and the relative loading of the fields, as well as to evaluate the dose to critical structures such as brain, brainstem, and optic structures.

Dose Fractionation Schedule

The dose schedule for low dose rate brachytherapy is 60 to 65 Gy during 5 to 7 days. The external-beam regimen for primary radiotherapy is 50 Gy in 25 fractions followed by a boost of 16 to 20 Gy in 8 to 10 fractions, depending on the size of the lesion. Postoperative radiotherapy consists of 50 Gy to elective tissue, 56 Gy to the operative bed, and 60 Gy to the tumor bed, with an optional boost to close or positive surgical margins, all given at 2 Gy per fraction. The dose regimens for IMRT are summarized in Table 39.3.

Maxillary Sinuses

Target Volume

Because maxillary cancers are usually diagnosed in a locally advanced stage and surgery is the primary therapy, most patients receive postoperative radiotherapy. Delineation of target volumes is based physical examination, pretreatment imaging, intraoperative findings (tumor extension relative to critical structures such as orbital wall, cribriform plate, cranial nerve foramina, and ease of resection), and pathologic findings (such as positive margin, perineural invasion).

IMRT is the preferred treatment method as it generally yields better dose distribution in terms of tumor coverage and normal tissue-sparing than 3D conformal radiotherapy. The CTV1 consists of the primary tumor bed with 1.0- to 1.5-cm margin of normal tissue. The CTV2 encompasses the operative bed, including the bony orbit after orbital exenteration and the ethmoid, frontal, and/or sphenoid sinuses if explored during surgery. A third CTV may be delineated to encompass the tract of cranial nerve V2 to the foramen rotundum if there is perineural invasion. A CTVHR (Table 39.3) may be outlined; for example, gross macroscopic residual tumor or positive margins, to which a higher dose may be delivered. An example of an IMRT plan for postoperative radiotherapy is shown in Figure 39.5.

For primary radiotherapy using IMRT, the prescription doses are 66 to 70 Gy to the gross tumor volume (prechemotherapy for those receiving systemic treatment), plus a 1- to 1.5-cm margin of normal-appearing tissue (CTV1), 59 to 63 Gy to other secondary clinical target volumes such as the rest of the involved sinus and wider region around the primary target, and 56 to
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57 Gy to the tracts of nerves if there is perineural invasion and to elective nodal regions. An example of an IMRT plan for primary definitive radiotherapy of a T4N0 squamous cell carcinoma is shown in Figure 39.6.

For postoperative radiotherapy using a 3D conformal technique, the initial target volume consists of the operative bed with 1- to 2-cm margins. The boost field consists of the primary tumor bed and areas at higher risk for recurrence such as positive resection margins or perineural invasion. Radiation is administered to the neck following node dissection if multiple nodes are involved and/or there is presence of extracapsular extension. Elective radiation of ipsilateral submandibular and subdigastric nodes is given in patients with squamous cell or poorly differentiated carcinoma.

Setup and Field Arrangement

The patient is immobilized in a supine position with the head slightly hyperextended to bring the floor of the orbit parallel to the axis of the anterior field. An intraoral stent is used to open the mouth and depress the tongue out of the radiation field. Following palatectomy, the stent can be designed to hold a water-filled balloon to obliterate the large air cavity in the surgical defect in order to improve dose homogeneity. An orbital exenteration defect can also be filled directly with a water-filled balloon to decrease the dose delivered to the temporal lobe. Marking of the lateral canthi, oral commissures, external auditory canals, and external scars facilitates target volume delineation. The planning CT scan should include the entire head in order to allow the use of vertex beams. The principles of target delineation and plan evaluation for IMRT of the maxillary sinus cancer are the same as those described for nasal cavity and ethmoid tumors.

For 3D conformal radiotherapy, a three-field technique consisting of an anterior and right and left lateral fields is used for tumors involving the suprastructure or extending to the roof of the nasal cavity and ethmoid cells. The lateral fields may have a 5-degree posterior tilt and 60-degree wedges. The relative loading varies from 1:0.15:0.15 to 1:0.07:0.07 depending on the tumor location and photon energy. For the initial target volume, the superior border of the anterior portal is above the crista galli to encompass the ethmoids and, in the absence of orbital invasion, at the lower edge of the cornea to cover the orbital floor. The inferior border is 1 cm below the floor of the sinus
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and the medial border is 1 to 2 cm (or more if necessary) across the midline to cover contralateral ethmoidal extension. The lateral border is 1 cm beyond the apex of the sinus or falling off the skin. The superior border of the lateral portals follows the floor of the anterior cranial fossa, the anterior border is behind the lateral bony canthus parallel to the slope of the face, the posterior border covers the pterygoid plates, and the inferior border corresponds to that of the anterior portal. The boost volume encompasses the tumor bed while sparing the optic pathway.

Anterior and ipsilateral wedge-pair (usually 45-degree wedges) photon fields are used for tumors of the infrastructure with no extension into the orbit or ethmoids. If necessary, the lateral portal can have a 5-degree inferior tilt to avoid beam divergence into the contralateral eye. Lateral-opposed photon fields are preferred for tumors of the infrastructure spreading across midline through the hard palate. If necessary, the fields can be slightly angled (5-degree inferior tilt from the ipsilateral side and 5-degree superior tilt from the contralateral side) to avoid irradiating the contralateral eye. The use of a half-beam with the isocenter placed at the level of the orbital floor and the upper half of the fields shielded further reduces exposure of the eyes by beam divergence.

The eyes and the optic pathway are of particular concern. With 3D conformal techniques, it is generally possible to shield the cornea in patients with limited involvement of the medial or inferior orbital wall to avoid keratitis. If the tumor invades the orbital cavity without necessitating orbital exenteration, care should be taken to avoid irradiation of the lacrimal gland to prevent xerophthalmia. It is important to keep the dose to the contralateral optic nerve as well as the optic chiasm below 54 Gy in 27 fractions to prevent bilateral blindness.

Treatment of the Neck

For squamous and undifferentiated carcinoma, elective neck irradiation is recommended (13). Ipsilateral upper neck treatment is delivered using a lateral appositional electron field (usually 12 MeV). With conventional radiotherapy, careful matching is required to prevent hot or cold spots. The superior border of the field slopes up from the horizontal ramus of the mandible anteriorly to match the inferior border of the primary portal posteriorly, leaving a small triangle over the cheek untreated. The anterior border is just behind the oral commissure, the posterior border is at the mastoid process, and the inferior border is at the thyroid notch (above the arytenoids). The nodal volume can also be covered using IMRT with sparing of the parotid gland. Alternatively, the primary tumor bed and the upper neck can be treated with IMRT with the isocenter above the arytenoids and matched to a separate unmodulated lower neck field. This allows sparing of the laryngeal structures using a larynx block.

If the maxillary sinus is being treated with conventional radiotherapy (non-IMRT), the central axes of the primary (sinus) fields and the opposed-lateral upper neck fields all are placed in the plane of the inferior border of the maxillary fields (i.e., usually 1 cm below the floor of the maxillary sinus). An independent collimator jaw is used to shield the caudal half of the maxillary fields and the cephalad half of the neck field. The junction between the primary and the neck fields can be moved during the course of treatment to reduce dose heterogeneity in this region. Portal reduction is made after 42 Gy and treatment to the posterior neck continues with abutting electron fields to the desired dose. The middle and lower neck is irradiated with an anterior appositional photon field matched to the inferior border of the opposed-lateral upper neck fields.

Dose Fractionation Schedule

Table 39.3 summarizes the dose regimens for IMRT. With 3D conformal techniques, the dose for postoperative radiotherapy at 2 Gy per fraction is 50 Gy for elective nodal treatment, 56 Gy to the operative bed, 60 Gy to the tumor bed if resection margins are negative, and 66 Gy if margins are positive. For primary radiotherapy, the total dose to the primary tumor at 2 Gy per fraction is 66 to 70 Gy. The contralateral optic nerve and chiasm are excluded from the field after a dose of 50 to 54 Gy. When the tumor invades structures adjacent to the optic chiasm, a dose of up to 60 Gy to the chiasm may be acceptable (potentially higher control probability with a still relatively low risk for visual impairment [44]) after clear discussion with the patient.

Follow-Up and Recurrences

Salvage is possible for some patients with persistent or recurrent lesions. In particular, recurrent cancers of the nasal vestibule remain curable with salvage surgery after primary radiotherapy or occasionally with salvage radiotherapy after primary surgery. Regional recurrences can be treated successfully with neck dissection with or without postoperative radiotherapy depending on pathologic features. Treatment options are limited for tumors that recur after combined modality therapy, although a few highly selected patients may qualify for reirradiation with curative intent. Cumulative doses of radiotherapy to neural tissues (spinal cord, brainstem, brain, optic structures) are the main limitation to reirradiation.

Most oncologists recommend a baseline physical examination together with CT or MRI for patients with nasal cavity or paranasal sinus tumors 3 months posttreatment. Common practice is to repeat clinical examination and imaging when indicated every 4 months for the first 3 years posttreatment, every 6 months for the fourth and fifth years posttreatment, and annually thereafter. In addition to evaluating for possible tumor recurrence, these follow-up visits are critical with respect to the identification and management of side effects of treatment.

Results of Treatment

The results of treatment have improved during the past 4 decades, with overall survival increasing progressively from 33% ± 18% in the 1960s, to 42% ± 15% in the 1970s, 54% ± 15% in the 1980s, and 56% ± 13% in the 1990s (p <.001) (17). In a systematic review of published series spanning 40 years, Dulguerov et al. (17) demonstrated a progressive improvement in outcome for all treatment modalities (surgery, surgery + radiotherapy, and radiotherapy).

Nasal Vestibule

Table 39.4 summarizes the results of six series of patients treated by brachytherapy, external-beam irradiation, or both, modalities (18,34,37,46,47). Either brachytherapy or external-beam radiotherapy cures up to 95% to 100% of small (up to 2 cm) tumors. When adequate doses of radiation are used, 70% to 80% of lesions >2 cm can be controlled. Although as many as 40% of patients with larger lesions who do not receive elective nodal irradiation will fail in the neck, most can be salvaged and ultimate regional control is excellent. Proper selection of radiation technique, dose, and fractionation results in a low rate of severe late complications.

An excellent analysis was conducted by the Groupe Europeen de Curietherapie (43). Of 1,676 carcinomas of the skin of the nose and nasal vestibule treated by brachytherapy or external-beam irradiation, the overall local control rate was 93%. Local control was dependent on tumor size (<2 cm, 96%; 2 to 3.9 cm, 88%; ≥4 cm, 81%), site (external surface, 94%; vestibule, 75%), as well as new versus recurrent tumors (95% vs.
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88%). Local control was independent of histology for tumors <4 cm, but for those >4 cm, basal cell carcinomas were more frequently controlled than were squamous cell carcinomas. There were few complications (necrosis, 2%). The local control rate with surgery was approximately 90%.

Nasal Cavity and Ethmoid Sinuses

Table 39.5 summarizes the results of relatively large series focusing on nasal cavity and ethmoid sinus tumors. Overall local control rates range from 60% to 80% (4,5,10). Results are best for patients with lesions confined to the nasal septum that are generally small and well controlled with primary radiotherapy. Interstitial brachytherapy alone may be the treatment of choice for such patients. Regional failure rates are low. In the MDACC series, nodal recurrence was approximately 5% in patients with nasal cavity tumors who did not receive elective nodal treatment. Complications such as soft tissue necrosis, nasal stenosis, and visual impairment are seen in 5% to 11% of patients.

The data on 783 of a total of 981 patients with nasal cavity cancer included in the Surveillance, Epidemiology, and End Results (SEER) database from 1988 through 1998 were recently analyzed (9). Squamous cell carcinoma was the most common tumor type (49.3%), followed by ENB (13.2%). More than half of the cases presented with a small primary tumor (T1), and only 5% had positive nodes at diagnosis. Overall mean (median) survival was 76 months and overall 5-year survival 56.7%. On multivariate analysis, male gender, increasing age, T stage, N stage, and poorer tumor grade adversely affected survival (p <.05). Radiotherapy was administered in 50.5% of patients, and also independently predicted poorer survival (p =.03), likely due to selection of patients with poor prognostic features such as perineural invasion, positive margins, or poor performance status (medically unfit for surgery) for radiotherapy. Five-year survival by tumor type, T stage, and N stage is shown in Table 39.6 (9). Five-year survival also correlates with tumor dedifferentiation: 75.3%, 61.9%, 47.6%, and 36.8% for well-, moderately, poorly, and undifferentiated cancers, respectively.

Esthesioneuroblastoma

Among the 783 cases of nasal cavity cancer extracted from the SEER database, 103 (13.2%) were ENB. Median survival was 88 months and overall 5-year survival 63.6% (9). Tables 39.7 and 39.8 summarize the results of treatment. The prognosis of patients with stage A disease is excellent. Overall, 30% of patients with stage B tumor died of the disease. About 60% of patients with stage C tumors died of the disease, primarily because of failure to control the primary tumor. Distant metastasis is uncommon (10%) even in locoregionally advanced disease.

Spaulding et al. (64) reported results for 25 patients treated at the University of Virginia Medical Center from 1959 through 1986 and followed for 2 years after therapy. There had been a gradual evolution of treatment with progressive introduction of craniofacial resections, complex field megavoltage radiation, and, for stage C disease, the addition of chemotherapy. Therefore, patients were divided into two groups, based on treatment era, for comparative analysis. Although the series is relatively small, it revealed two interesting findings for this rare disease: (a) extensive craniofacial resection does not appear to confer a major advantage over wide local excision for patients with stage B lesions, and (b) the addition of chemotherapy to craniofacial resection and radiotherapy for patients with stage C tumors may yield a higher disease-specific survival.
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An analysis of 72 sinonasal neuroendocrine tumors treated at MDACC between 1982 and 2002 included a spectrum of histologies: ENB (31 patients), sinonasal undifferentiated carcinoma (SNUC, 16 patients), neuroendocrine carcinoma (NEC, 18 patients), and small cell carcinoma (7 patients). The overall survival at 5 years was 93.1% for patients with ENB, 62.5% for SNUC, 64.2% for NEC, and 28.6% for small cell carcinoma (p = .0029; log-rank test). The local control rate at 5 years also was superior for patients with ENB (96.2%) compared with patients who had SNUC (78.6%), NEC (72.6%), or small cell carcinoma (66.7%) (p = .04). The regional failure rate at 5 years was 8.7% for patients with ENB, 15.6% for SNUC, 12.9% for NEC, and 44.4% for small cell carcinoma. The corresponding distant metastasis rates were 0% for ENB, 25.4% for SNUC, 14.1% for NEC, and 75.0% small cell carcinoma. ENB had excellent local and distant control rates with local therapy alone (58). Eight patients with ENB were treated at MDACC during the past 3.5 years with surgery and adjuvant radiotherapy using IMRT to 60 Gy. One patient had stage B disease and seven had stage C, of whom five had intracranial extension. There were no local recurrences and one nodal recurrence was salvaged surgically. All eight patients were alive with no evidence of disease at the last follow-up.

Maxillary Sinuses

For patients with carcinoma of the maxillary sinuses, the combination of surgery and radiation yields 5-year local control and survival rates of 44% to 80% (Table 39.9). These rates are better than those achieved with either surgery or radiotherapy alone.
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For radiotherapy alone, the 5-year local control rate ranges from 22% to 39% and the 5-year overall survival rate is 22% to 40%.

Sequelae of Treatment

Soft Tissue and Bone

The formation of nasal cavity synechiae (fibrous mucosal bands causing airway stenosis) can be prevented by intermittent dilation of the nasal passages with a petroleum-coated cotton swab until mucositis has resolved. Dry mucous membranes can be managed symptomatically with saline nasal spray. Soft-tissue or cartilage necrosis is uncommon after therapy with an estimated incidence of 5% to 10% (19,35,52,53).

Eyes and Optic Pathway

Chronic keratitis and iritis (“dry-eye syndrome”) can develop after radiotherapy if tumor extension to the orbital cavity mandates irradiation of the lacrimal gland to doses of more than 30
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to 40 Gy (53). Without lacrimal irradiation, fewer than 20% of patients treated with up to 55 Gy to the cornea develop chronic corneal injury (29). There is an approximately 5% risk (at 5 years) of cataract formation after doses of up to 10 Gy to the lenses using conventional fractionation; this risk increases to 50% at 5 years after 18 Gy (21).

Radiation retinopathy is rare after doses of less than 45 Gy, but the incidence increases to about 50% after doses of 45 to 55 Gy (52). The reported incidence of optic neuropathy is <5% after 50 to 60 Gy but increases to around 30% for doses of 61 to 78 Gy. The parameters that influence the risk of radiation-induced optic neuropathy were recently analyzed in 273 patients treated between 1964 and 2000 in whom the radiation fields included the optic nerves and/or chiasm (46). The likelihood of developing optic neuropathy was primarily influenced by the total dose, but fraction size was marginally significant. The 5-year rates of freedom from optic neuropathy were 95% for doses ≤63 Gy treated once daily, 98% for doses ≤63 Gy treated twice daily, 78% for doses >63 Gy treated once daily, and 91% for doses >63 Gy treated twice daily. On multivariate analysis, the risk of optic neuropathy was correlated with increasing total dose (p =.0047). A trend was seen with increasing patient age (p =.091), once daily versus twice-daily fractionation (p =.068), and overall treatment time (p =.097). When the target volumes include the optic pathway, special attention must be paid to hot spots and dose per fraction.