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.

40

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Chapter 40

Salivary Glands

Chris H. J. Terhaard

The salivary glands consist of the three large, paired major glands—parotid, submandibular, and sublingual (Fig. 40.1)—and many smaller, minor glands located throughout the upper aerodigestive tract. Salivary gland malignancies make up only approximately 0.4% of all cancers, and account for less than 5% of the annual incidence of head and neck malignancies in the United States. The international variation in the incidence is between 0.4 and 2.6/100 per year (72), with a mean of approximately 1/100. No significant change in incidence has been shown in the past decades in the United States and Sweden (72,97).

Anatomy

Major Salivary Glands

Parotid Gland

The parotid gland is located superficial to and partly behind the ramus of the mandible and covers the masseter muscle. Superficially, it overlaps the posterior part of the muscle and largely fills the space between the ramus of the mandible and the anterior border of the sternocleidomastoid muscle. One or more isthmi that wrap around the branches of the facial nerve connect the superficial and deep lobes of the gland. The nerve enters the deep surface of the gland as a single trunk, passing posterolateral to the styloid process. It usually leaves the gland as five or more branches, emerging at the anterior, upper, and lower borders of the gland. The facial nerve runs superficial to the main blood vessels that traverse the gland but is interwoven within the glandular tissue and its ducts. Thus, removal of all or part of the parotid gland demands meticulous dissection if the nerve is to be spared.

The parotid gland contains an extensive lymphatic capillary plexus, many aggregates of lymphocytic cells, and numerous intraglandular lymph nodes in the superficial lobe. Lymphatics drain from more lateral areas on the face, including parts of the eyelids, diagonally downward and posteriorly toward the parotid gland, as do the lymphatics from the frontal region of the scalp. Associated with the gland, both superficially and more deeply, are parotid nodes. These drain downward along the retromandibular vein to empty in part into the superficial lymphatics and nodes along the outer surface of the sternocleidomastoid muscle and in part into upper nodes of the deep cervical chain. Lymphatics from the parietal region of the scalp drain partly to the parotid nodes in front of the ear and partly to the retroauricular nodes in back of the ear, which, in turn, drain into upper deep cervical nodes (46) (Fig. 40.2).

Submandibular Gland

The submandibular gland largely fills the triangle between the two bellies of the digastric and the lower border of the mandible and extends upward deep to the mandible. It lies partly on the lower surface of the mylohyoid and partly behind the muscle against the lateral surface of the muscle of the tongue, the hypoglossus. The submandibular gland has a larger superficial part, or body, and a smaller deep process. The inferior surface is adjacent to the submandibular lymph nodes, and the deep process of the submandibular gland lies between the mylohyoid laterally and the hyoglossus medially, and between the lingual nerve above and the hypoglossal nerve below (7). Bimanual palpation with one finger in the floor of the mouth and one under the edge of the mandible facilitates clinical detection of masses in this gland.

A rich lymphatic capillary network lies in the interstitial spaces of the gland. From the lateral and superior portions of the gland, lymph flows to the prevascular or preglandular submandibular lymph nodes. The posterior portion of the gland gives rise to one or two lymphatic trunks, which follow the facial artery and go directly to the anterior subdigastric nodes of the internal jugular chain (40,43). The nodes overlying the submandibular gland, followed by the subdigastric and high midjugular lymph nodes, are those involved in nodal metastases.

Sublingual Gland

This smallest of the three major salivary glands, along with many minor salivary glands, lies between the mucous membrane of the floor of the mouth above and the mylohyoid muscle below, the mandible laterally, and the genioglossus muscles of the tongue medially (Fig. 40.1). This is a rare site for malignant neoplasms; they are difficult to distinguish from cancer of the floor of the mouth accounting for fewer than 2% of all reported cases of salivary gland tumors (72,93). The sublingual gland drains either to the submandibular lymph nodes or more posteriorly into the deep internal jugular chain between the digastric and omohyoid muscles. Rarely, the lymphatics of the sublingual gland drain into a submental node or supraomohyoid jugular node (40).

Minor Salivary Glands

Minor salivary glands are widely distributed in the upper aero-digestive tract, palate, buccal mucosa, base of tongue, pharynx, trachea, cheek, lip, gingiva, floor of mouth, tonsil, paranasal sin-uses, nasal cavity, and nasopharynx.

Epidemiology

Seventy percent of all salivary tumors arise in the parotid gland, 8% in the submandibular gland, and 22% in the minor salivary glands (93). The proportion of malignant tumors increases from parotid (25%) to submandibular (43%) to minor salivary glands (65%) (57,93). There is a preponderance of benign tumors in women; malignant tumors exhibit an equal sex distribution. Patients with benign tumors are younger (mean age, 46 years) compared with those with malignant tumors (mean age, 54 years), with a trend to an older age for submandibular and minor salivary gland locations (93). Two percent to 3% of salivary neoplasms occur in children, in whom half of the tumors are malignant (21). The majority of cancers are located in

the parotid gland, with mucoepidermoid cancers predominating (88).

Etiologic factors are not clearly defined. Nutrition may be a factor because Eskimos in the Arctic, who have low intake of vitamins A and C, have a high incidence (56). Cigarette smoking and alcohol consumption is in general not related with salivary gland cancer (68), although cigarette consumption more than 80 pack-years may contribute to salivary gland cancer (98). Irradiation can also be a cause, as evidenced by the increased incidence in survivors of the atomic bombs dropped on Hiroshima and Nagasaki, and in those irradiated to the head and neck for benign conditions during childhood (67,83,84,111). Saku et al. (83) studied salivary gland tumors in atomic bomb survivors of Hiroshima and Nakasaki. Two-thirds of all cases were parotid, and the remainder was equally distributed between submandibular and minor salivary glands. Mucoepidermoid cancer and Warthin's tumor (benign) were particularly elevated compared with nonexposed persons, and disproportionately high at high radiation doses. Modan et al. (67) found a clear dose-response effect in a matched control study of patients who had low-dose head–neck irradiation in childhood; there was a 2.6-fold increase of benign tumors and a 4.5-fold increase of cancer. The majority of these tumors are mucoepidermoid cancers (84,111); however, less than 1% of salivary gland tumors may be caused by former irradiation (8).

Workers in various occupations experience an increased risk of salivary gland cancer (47). For women employed as hairdressers or working in beauty shops, a significant elevated risk was observed in a study by Swanson and Burns (98). A correlation of incidence with ultraviolet exposure remains controversial (97,98).

Women with salivary gland cancer may have a 2.5 elevated breast cancer risk (50), probably confined to women with salivary gland cancer before age 35 (97). After treatment for salivary gland cancer, an increased risk for subsequent oropharyngeal, thyroid, and lung cancer is noted (97).

Natural History

Local invasion is the initial route of spread of malignant tumors of the salivary glands, depending on location and histologic type. For parotid tumors, this may result in fixation to structures in around 20% of cases (75). Skin invasion is more often seen in parotid tumors (10%), compared with submandibular tumors (3%) (101).

Approximately 25% of patients with a malignant parotid salivary gland tumor present with facial palsy from cranial nerve invasion (31,75,93,100,105).

A detailed study of the Dutch Head and Neck Oncology Group (NWHHT) concerning patients with a salivary gland malignancy found an overall incidence of clinically positive nodes of 14% and clinically occult, pathologically positive nodes in an additional 11% of patients (101). This percentage depends on the number of neck dissections performed, the tumor location, histology, and T-stage. The number of elective neck dissections performed varies between the tumor locations. Stennert et al. (94) performed a neck dissection in all malignant parotid tumors and found 53% unilateral positive nodes and 0% contralateral nodes. In selected patients in other studies, the percentage positive nodes varied between 20% (115) and 38% (100). Lymph

node involvement for parotid malignancies, combining clinical and pathologic information, is around 25% (10,62,79,100,105). Resection of submandibular tumors is combined with a (partial) neck dissection in most cases. Pathologic neck nodes may be seen in up to 42% of cases (100). Salivary gland tumors arising in the oral cavity produce an incidence of cervical node metastases of less than 10% (57,65,74,100). Nasopharyngeal salivary gland tumors have a high risk of occult metastases (50%) (85). The risk of positive findings in the neck may be based on a combination of T-stage and histology (79,100). The highest risk is seen for squamous cell, undifferentiated cancer, and salivary duct cancer (79,100). There is an intermediate risk for mucoepidermoid cancer and a low risk for acinic cell, adenoid cystic carcinoma, and carcinoma ex pleomorph adenoma (100). A 15% risk is found for T1 tumors, 26% for T2, and 33% for T3–4 (100). An example of a rating scale to estimate the risk of positive neck nodes, based on tumor location, T-stage, and histologic type, is shown in Table 40.1.

Distant metastases overall are encountered in 3% of patients at presentation and in 33% after 10 years (101). They are fairly common with adenoid cystic, salivary duct, squamous cell, and undifferentiated carcinomas; in the case of adenoid cystic carcinomas, they may occur quite late in the course of the disease, without recurrence of the primary tumor (42,52,74,92,101). Distant metastases are primarily to lung, bone, and occasionally to the liver (101). Reported incidence of distant metastases in patients with adenoid cystic carcinoma after 10 years of follow-up is around 40% (64,92,101). Five years after diagnosis of distant metastases of adenoid cystic carcinoma, more than one third of the patients are still alive; 10% are alive after 10 years. An update of the survival data of the NWHHT study after diagnosis of distant metastases of salivary gland cancer is shown in Figure 40.3.

Clinical Presentation

Three of four parotid masses are benign (93). Patients most often have a painless, rapidly enlarging mass, often present for years before a sudden change in its indolent growth pattern prompts the patient to seek medical attention. Duration of clinical symptoms before diagnosis may last more than 10 years (93,101). For malignant tumors, the median duration of clinical symptoms generally is shorter (3 to 6 months) (9,101) compared to that of benign tumors, although for some minor salivary gland tumors, median periods of 2 year have been reported (65,85).

Pain is more frequently associated with malignant disease (93). Although as many as one third of parotid cancers may have facial nerve involvement, only 10% to 20% of patients complain of pain (75,93,101). Pain may appear with involvement of deeper structures (masseter, temporal, and pterygoid muscles). Rarely, tumors of the parotid may involve the base of skull and cause intractable pain and paralysis of various cranial nerves.

The signs and symptoms associated with tumors of the minor salivary glands vary because of their diverse locations. The distribution of presenting sites for 492 cases of minor salivary gland tumors, 88% of which were malignant, is shown in Table 40.2 (93). Most are intraoral, and a painless lump is the most common presenting symptom. For tumors arising in the nasal cavity or sinuses, facial pain is the most common presenting symptom, followed by nasal obstruction. Laryngeal primary tumors most frequently cause hoarseness or voice change.

Clinical features suggesting a malignant salivary gland tumor are rapid growth rate, pain, facial nerve palsy, childhood occurrence, skin involvement, and cervical adenopathy.

Diagnostic Work-Up and Staging

Major Salivary Glands

The diagnostic work-up of major salivary gland tumors includes a careful history and physical examination, with particular

attention to signs of local fixation or regional adenopathy. Computed tomography (CT) scans are useful in evaluating the extent of lesions involving the parotid gland, especially the deep lobe. Magnetic resonance imaging (MRI) is superior to other modalities, especially when malignancy is suspected (Fig. 40.4). T1-weighted images are excellent to assess the margins, deep extent, and patterns of infiltration because the (fatty) background of the gland is hyperintensive. In general, benign tumors are hyperintensive, and malignant tumors are intermediate or low intensivity at T2-weighted MR images (73,114). The MRI has a sensitivity of 87% and a specificity of 94% (73). Perineural invasion of adenoid cystic carcinoma may be evaluated with both CT (foraminal enlargement) and MRI (fat-suppressed T1-weighted images). Such findings may well change the surgical approach and treatment regimen (15,114).

Fine-needle aspiration in the diagnosis of parotid and submandibular salivary gland tumors is a reliable procedure. The sensitivity for malignancy varies between 80% and 90%; the specificity is more than 90% (20,73,76,95). The negative predictive value for malignancy, however, is around 70% to 75% (20,73). False-negative findings may be seen as result of lack of representative material or a cyst. In these cases, ultrasound fine-needle aspiration is advised (76). The relative low negative predictive value of fine-needle aspiration will be improved if MRI and fine-needle aspiration are combined (74). Fine-needle aspiration has been quite accurate in the diagnosis of benign salivary gland tumors (20,95).

The sixth edition of the manual of the American Joint Committee on Cancer (2) and the sixth edition of the classification system of the International Union Against Cancer (90) are identical for major salivary glands (Table 40.3). They are based on size, extension, and nodal involvement. Relative survival rates for major salivary gland cancer according to stage are shown in Figure 40.5.

Minor Salivary Glands

Various radiographic studies may be used, including plain films, to ascertain bone erosion in advanced lesions, and CT and MRI scans may be used to evaluate depth and contiguous involvement. The definitive diagnostic procedure is an excisional biopsy, particularly if malignancy is clinically expected. Unplanned incisional biopsies should be avoided, and fine-needle biopsies are impractical because of the polymorphism of most malignant salivary gland tumors.

A formal staging system has not been developed for minor gland tumors. The same staging system for minor salivary glands as for squamous cell carcinoma in sites other than the parotid or submandibular glands may be used. The American Joint Committee on Cancer and International Union Against Cancer classification and stage regrouping system has been reported to be a major long-term outcome predictor in minor salivary gland carcinoma (104).

Pathologic Classification

The histologic classification of salivary gland neoplasia is very demanding for the head and neck pathologist. In 1991 the World Health Organization classification for salivary gland tumors was expanded. Various types of carcinomas were distinguished based on recognition, prognosis, and treatment, discussed more in detail by Seifert and Sobin (87) (Table 40.4). Classification may be difficult, as shown in a re-evaluation of 101 intraoral salivary gland tumors by experienced pathologists; major disagreement was seen in 8 and there was minor disagreement in 33 (103).

Neoplastically transformed myoepithelial cells play a role in the development of monomorphic and pleomorphic adenomas, adenoid cystic carcinomas, mucoepidermoid carcinomas, and the rare myoepithelomas (7). The reserve cell system of the intercalated and excretory duct is thought to be the site of origin of most neoplasms (7).

Salivary gland carcinomas may be graded as low and high malignant, particularly for mucoepidermoid tumors. However, there is a disparity for grading, even among experienced pathologists (13). Low-grade mucoepidermoid, polymorphous low-grade adenocarcinoma (PLGA), epithelial-myoepithelial, and acinic cell carcinomas comprise a group of low-to-moderate malignancy; high-grade mucoepidermoid, malignant mixed, adenoid cystic, squamous, undifferentiated, and salivary duct carcinomas represent more high-grade malignancies (105). The percentage of the histologic subtypes varies from series to series, and from the localization of the tumor (Fig. 40.6). In parotid tumors in children and adults, the most common malignant subtype is the mucoepidermoid (10,21,37,88,91,108). Acinic cell cancer derives from cells of the terminal ducts and intercalated ducts. Grading for acinic cell cancer is controversial (45). Most tumors (86%) are located in the parotid gland (Fig 40.6) (45). Adenoid cystic carcinoma is most common in minor salivary glands (Fig. 40.7) (57,74,101,104), followed by

the submandibular gland (Fig. 40.6) (11,96,101,108). Perineural invasion is common in adenoid cystic carcinoma (107). The adenoid cystic variety has a tubular pattern that has been associated with the best prognosis, a cribriform pattern with an intermediate prognosis, and a solid pattern with the worst prognosis (28). The PLGA and salivary duct carcinomas are the most common new subtypes of the World Health Organization 1991 classification. PLGA is a solid, ovoid, nonencapsulated mass with a highly variable growth pattern (Fig. 40.8). Most are located in the palate, and the prognosis generally is good (17,29). Salivary duct carcinoma resembles ductal breast cancer morphologically (Fig. 40.8). They derive from excretory duct cells. They are usually located in the parotid gland and are highly aggressive (42,48,52). There is also a low-grade subtype (23).

Prognostic Factors

A number of prognostic variables have been studied in the management of salivary gland cancer. In these studies, multivariate analyses have been performed considering locoregional control, distant metastases, and survival. Results of studies with sufficient number of patients and follow-up have been summarized in Table 40.5. Local control and overall survival is influenced by site, favoring tumors of the oral cavity (101,102). T- and N-stages are independent variables for locoregional control, distant metastases, and survival, regardless of site (10,37,57,58,62,65,66,74,75,92,101,102,105). In the NWHHT study, histologic type was an independent prognostic factor for distant metastases (101).

Oncogene expression has been evaluated in the search for additional prognostic factors. Expression of the oncoprotein p53 was found in an Italian study to be higher in malignant tumors than in benign tumors (35). Furthermore, tumors with moderate-to-high expression of p53 were more frequently associated with regional and distant metastasis and a lower disease-free and overall actuarial survival rate, compared with patients with no p53 expression. Univariate and multivariate analyses confirmed the independent prognostic value of p53 expression. Vascular endothelial growth factor significantly correlates with p53 expression and is an independent prognostic factor

for survival for salivary gland cancer (61). Overexpression of HER-2/neu was seen in approximately one third of mucoepidermoid carcinomas in a series of 50 parotid gland cancers studied at the University of Southern California (78) and in 20% in a series of 50 salivary duct carcinomas in a study from Germany (52). Overexpression was seen and appeared to be an independent marker of poor prognosis. It also has been similarly associated with poor prognosis in carcinomas of the breast, ovary, and endometrium. Another molecular feature studied in relationship to prognosis was the DNA content in adenoid cystic carcinomas. DNA aneuploidy is correlated with the solid type, and thus with poor prognosis (28). Franzen et al. (32) found a correlation of grade with aneuploidy as well as stage.

Major Salivary Glands

The survival of patients with submandibular cancers is inferior to that of parotid cancers according to a study by Spiro et al. (91). Extraglandular extension (10,37) and skin invasion (70,101,105) in parotid cancers results in decreased disease-free survival. More advanced age was found to be a negative prognostic factor for locoregional control in some studies (58,75,79) and for disease-free and overall survival in most studies (10,58,62,75,91,105,106). Impairment of function of the facial nerve is a known prognostic factor, not only influencing locoregional control (37,70,101), but also disease-free survival (36,62,70,105). Pain at presentation may be associated with reduced disease-free survival (105). Perineural invasion and pain are closely related: not pain, but perineural growth, in some studies, is an independent prognostic factor for distant metastases (101) or disease-free survival (37,44).

The importance of histologic subtype for major salivary gland cancer varies in published studies. In most studies, histologic types are subdivided into low and high grade. The main prognostic significance of grading relates to disease-free survival (10,62), although grade was not a prognostic factor in most studies. The best prognosis is seen for acinic cell and (low-grade) mucoepidermoid cancer (91,101), the worst for undifferentiated (70,101) and squamous cell cancer (91,101). At the Netherlands Cancer Institute, a prognostic score for patients with parotid carcinoma was developed and validated adequately with the NWHHT database (105,106). The preoperative prognostic score was based on a weighted combination of prognostic factors (age, pain, clinical T- and N-stages, skin invasion, and facial nerve dysfunction); histology and grading were not incorporated. Four subgroups were formed with markedly different prognoses. In the postoperative score, perineural invasion and positive surgical margins were also included. Positive or close surgical margins result in an increase in local recurrence rate(77,96,101,102).

Radiation therapy in addition to surgery improves locoregional control in patients with adverse prognostic factors (70,75,81,100,102). Improvement of survival has only been shown in two studies (11,70), and for stage III and IV major salivary glands in a matched-pair analysis (4).

Minor Salivary Glands

The poorest prognosis is associated with adenoid cystic carcinoma (9,65). Stage, base of skull involvement, and bone invasion are risk factors for locoregional recurrence and survival in minor salivary gland cancers (9,24,25,57,65,77). Locoregional control may be improved by adding postoperative radiotherapy (74).

General Management

The general management of salivary gland malignancies in most patients includes surgical excision followed by radiation therapy for unfavorable prognostic factors (Table 40.5) (3). Postoperative radiotherapy to enhance local control is recommended for T3–4 tumors, close or incomplete resection, bone involvement, perineural invasion, high-grade cancer, and

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recurrent cancer (9,37,58,70,96,101). To date, adjuvant chemotherapy has not been considered efficacious. For advanced, inoperable, and recurrent salivary gland cancers, primary neutron therapy may lead to superior local control rates, compared with primary photon therapy, without evidence of improved survival rates (24,49,60). The use of conventional radiation therapy along with hyperthermia has been reported to have similar efficacy in this patient population (34).

Major Salivary Glands

Surgical technique depends on location and extent of primary disease and regional adenopathy. Preservation of the facial nerve, at least partially, followed by postoperative radiotherapy is the preferable treatment unless the facial nerve is involved by tumor (6). Aggressive surgery does not improve disease-free survival. A decrease in extended surgery, resulting in a decrease of sacrifice of the facial nerve, has been shown in the course of years (91). Cable facial nerve grafting with the greater auricular or sural nerve graft decreases the incidence of facial palsy postoperatively, especially if branches and not the main trunk are involved (14,56). Adjuvant postoperative radiotherapy has no negative effect on facial nerve function (14).

Surgical treatment includes neck dissection in cases of clinically positive nodes, followed by postoperative radiotherapy (100). The risk of occult nodal disease depends on T-stage and histologic type. As shown in the scoring system in Table 40.1, the decision to treat the neck for parotid tumors will be indicated by a score of at least 4 (100). When local prognostic factors indicate postoperative radiotherapy, no elective neck dissection has to be performed; the neck nodes will also be irradiated (30,94). Parotid tumors with facial nerve weakness are associated with

frequent occult neck nodes; elective treatment is also indicated (30). In most cases, elective neck dissection of level I-III combined with a local resection is performed for submandibular tumors. There is no indication for neck dissection for T1 acinic or T1 adenoid cystic tumors (Table 40.1) (96,100).

Minor Salivary Glands

The treatment of minor salivary gland tumors varies with location but usually involves an attempt at adequate surgical excision first. Irradiation has been used in surgically inaccessible sites or combined with surgery because of locally aggressive tumor behavior and the occurrence of incomplete resection (9,38,74,101). For tumors arising in the palate, tongue, floor of the mouth, oral cavity, or oropharynx, surgical exposure is readily available, and resection usually can be accomplished with acceptable morbidity. Tumors arising in the posterior nasal cavity, nasopharynx, or sphenoid region, however, are relatively inaccessible and are mostly treated with radiation therapy (38). Elective neck treatment is usually not indicated (38,74,100), except for tumors of the floor of mouth, oral tongue, pharynx, and larynx (74,85,115). Surgery alone may be used to treat early-stage hard palate lesions without evidence of positive margins, perineural spread, or bone invasion; simple excision must be avoided (9). Patients with adenoid cystic carcinoma can have a long natural history with late recurrences (38), and consideration should be given to careful surgical reconstruction and rehabilitation because even patients who are not cured can live many years before dying of disease (Fig. 40.3) (101). Occasionally, a patient may present after simple excision (shelling out) of a lesion and the pathologic examination shows adenoid cystic carcinoma. If re-excision would cause significant functional or cosmetic sequelae, irradiation alone may be used (74). However, simple excision is not recommended as the initial management of these tumors because of the potential for a significant volume of residual disease.

Radiation Therapy Techniques

Pleomorphic Adenoma

The pleomorphic adenoma (benign mixed tumor) is histologically benign, occurs frequently in a relatively young population, and comprises 65% to 75% of all parotid epithelial tumors (57,91). Standard therapy has been conservative (superficial) parotidectomy, with recurrence rates of about 0% to 5% (112). Simple excision results in a high recurrence rate of around 25% as focal capsular exposure occurs in virtually all cases (112). In the past at some institutions, local excision and radiation therapy have been used to lower the frequency of facial nerve injury and Frey's syndrome (22). Dawson and Orr (22) reported results for 311 patients. They found a 2.5% recurrence rate at 10 years and an additional 5.5% by 20 years. None of the patients had malignant recurrences at 10 years, 0.5% had such recurrences at 15 years, and 3% had recurrences at 20 years. The later recurrences were more likely to show malignant transformation. The authors concluded that the primary treatment should be surgery because of the patient's young age, benign histology, and the remote possibility of subsequent radiation-induced malignancy. However, certain patients may be referred for radiation therapy (63). Indications for postoperative irradiation may include recurrent disease; microscopically positive margins after surgical resection; and large, deep-seated lesions that may not allow complete surgical excision with adequate margins or would require sacrificing the facial nerve (16,22,63,80). Radiotherapy may decrease the risk of a second recurrence in case of multinodular recurrence only, not for uninodular disease (81). The entire parotid area should be irradiated with a dose of 50 to 60 Gy in 5 to 6 weeks.

Parotid Gland

The volume of irradiation is determined by pathologic findings, such as perineural invasion of a major nerve. Typically, the entire ipsilateral parotid gland is delineated on the postoperative CT scan performed in a stabilization device (37,71). The delineation of the clinical target volume will be individualized based on the extent of the disease and surgery (37). The parapharyngeal space and the infratemporal fossa have to be covered adequately (71). The primary treatment volume includes the ipsilateral subdigastric nodal areas because the inferior pole of the parotid lies in this region (3). In general it is not necessary to treat the scar to full skin dose because only 1% of the patients have a scar failure (58). For very superficial localized tumors and in case of skin invasion, a bolus over the scar is required. In tumors with named perineural invasion (e.g., adenoid cystic carcinoma), it is important to cover the cranial nerve pathways from the parotid up to the base of the skull (39,96). Focal perineural invasion only is not an indication for routine inclusion of the nerve pathways (39). No clear relationship between dose and local control has been found. In general, a dose of at least 60 Gy postexcision is recommended (39,71,100), and at least 66 Gy (33 fractions) for positive margins (37,39).

The ipsilateral neck is treated after a neck dissection has been performed for positive nodes; level I-V should be included (100). There is no indication for bilateral elective neck treatment (94). The recommended postoperative dose for positive nodes is at least 60 Gy (30 fractions) (100). Elective irradiation of the neck should be considered for advanced T-stage, certain histologic subtypes (Table 40.1), facial nerve dysfunction at presentation, and recurrent disease. At least level Ib, II, and III should be included (5,30,100). A dose of around 46 to 50 Gy is recommended (3,37,100).

Three basic radiation therapy approaches are used, depending on available equipment: Conventional, three-dimensional conformal radiation therapy (3DCRT) planning procedure, and intensity-modulated radiation therapy (IMRT) planning. The first involves unilateral anterior and posterior wedged pair fields using 60Co or 4- to 6-MV photons (Fig. 40.9A). A slight inferior angulation of the beams avoids an exit dose through the contralateral eye. A simpler technique uses homolateral fields with 12- to 16-MeV electrons in combination with photons (37,41,113). Usually, 80% of the dose is delivered with electrons and 20% with 60Co or 4- to 6-MV photons to spare the opposite salivary gland, reduce mucositis, and decrease the skin reaction produced by electrons (Fig. 40.9B). Yaparpalvi et al. (113) compared nine conventional treatment techniques. Ipsilateral wedge pair technique with 6-MV photons, wedged anteroposterior and posteroanterior and lateral technique with 6-MV photons, and mixed beam using 6-MV photons and 16-MeV electrons (1:4 weighted) were most optimal, considering dose homogeneity within the target and dose to normal tissues. Electron beam (9 to 12 MeV) and tangential photon fields are effective conventional techniques for sparing the underlying spinal cord (from doses more than 45 Gy) and the opposite parotid gland in elective neck irradiation. Conventional techniques do not allow for tissue heterogeneity (air cavity, dense bones, and tissues); underdose and overdose may be seen.

After outlining of the target volumes and critical normal tissues on the planning CT scan, a more conformal 3DCRT plan by the use of geometrically shaped beams of uniform intensity may be reached (71). More normal tissue may be spared with this technique (71). Probably the most conformal radiation technique is IMRT. It can produce convex dose distributions and steep dose gradients. Five- to seven-field inverse IMRT allows excellent coverage of the tumor with sparing of mandible,

cochlea, spinal cord, brain, and oropharynx (12,71), compared with conformal 3DCRT. Figure 40.10 shows a comparison of 3DCRT and IMRT planning for a postoperative radiotherapy plan for a parotid cancer treated with a dose of 66 Gy. The mean dose to the mastoid, meatus acusticus externus, and contralateral parotid gland was 53 and 43 Gy, 57 and 51 Gy, 1 and 9 Gy, for 3DCRT and IMRT, respectively. The maximum dose to the cochlea was 39 and 32 Gy, respectively.

Submandibular Gland

Except for small acinic cell and adenoid cystic cancer (Table 40.1), the neck nodes level I-IV (5) should be irradiated electively, following the indications outlined for parotid tumors; technical considerations are similar. Bilateral fields may be required for tumor extension toward the midline. If there is no gross residual tumor or perineural invasion, 50 Gy in 5 weeks should be adequate for microscopic disease. If there is named perineural invasion of a major nerve, a tumor dose of 60 to 66 Gy in 6 to 6.5 weeks is recommended, and the nerve path to the base of skull should be treated, preferably by 3DCRT or IMRT. For an adenoid cystic carcinoma of the submandibular gland with only focal perineural invasion, an attempt to encompass the base of the skull would require a significant change in the treatment volume and may not be warranted because of potential morbidity and the low rate of relapse at that site (38). An example of 3DCRT for a T2 adenoid cystic carcinoma of the submandibular gland is shown in Figure 40.11.

Minor Salivary Glands

The radiation therapy technique for treating minor salivary gland tumors depends on the area involved and is similar to the treatment for squamous cell carcinomas in these areas, with two significant exceptions. First, when a named branch of a cranial nerve is involved by adenoid cystic carcinoma, the nerve pathways to the base of the skull should be electively treated. When only focal perineural invasion of small unnamed nerves is present, treatment of the base of the skull depends on the site. Second, for tumors of the palate or paranasal sinuses, the base of the skull is included because of its proximity to the tumor bed. In case of an adenoid cystic carcinoma with perineural invasion, IMRT may reduce the high-dose volume, compared to conventional bilateral opposed fields; Figure 40.12 shows an example for a patient with a minor salivary gland cancer of the palate. IMRT is a useful strategy for irradiating minor salivary gland sites such as the ethmoid sinuses while sparing the optic pathways (19).

Also, because the incidence of lymph node metastases is usually lower than that for squamous cell carcinomas of similar size, the radiation therapy fields are rarely extended to cover such areas if there are no palpable lymph node metastases. Indications for treating the neck are a primary tumor that arose in the tongue, floor of the mouth, pharynx, or larynx (74), and the neck was not dissected, or after resection of metastatic neck lymphadenopathy.

For patients receiving postoperative irradiation after surgical resection, a dose of 60 Gy is given for negative margins and 66 Gy for microscopically positive margins. For gross residual disease after surgery or for lesions treated with irradiation

alone, a total dose of 70 Gy is recommended at 2 Gy per fraction.

Results of Therapy

Surgery Plus or Minus Postoperative Radiotherapy

Tables 40.6, 40.7 and 40.8 list local control rates and 5- and 10-year survival rates for several series reporting the surgical, irradiation, and combination treatment of carcinomas of the major and minor salivary glands. Little adverse effect of delay between surgery and radiotherapy may be predicted for what are, in general, slow-growing salivary gland cancers. In only two studies, one concerning submandibular cancer (96) and another for minor salivary gland (38), impaired locoregional control rates were seen for a delay of more than 6 weeks, which was not confirmed in the Dutch study (100). The prognosis for children with a malignant salivary gland cancer (mostly mucoepidermoid cancer of the parotid gland) is excellent, with a 10 year overall survival of more than 90% (88). Most are treated with surgery alone because of the possible risk on radiation-induced malignancies.

Long-term follow-up is recommended because failures may appear after 5 years, especially for minor salivary gland tumors (17,29,57,101). Recurrent tumors in general are more difficult to control than are primary ones, so high initial locoregional control rates should be the goal (101). Because of high rates of local failure of approximately 40% for parotid, 60% for submandibular, and 65% for minor salivary glandswith surgery alone in the past (93), many institutions have advocated postoperative irradiation especially to reduce the incidence of local failure. Local tumor control appears to be improved by the combination of surgery and irradiation, although randomized, controlled trials have not been performed. Evidence of a positive role of postoperative radiotherapy is based on retrospective studies and a matched-pair analysis. In the study by Armstrong et al. (4), postoperative radiotherapy significantly improved locoregional control (from 17% to 51% for stage III-IV), not for stage I and II major salivary gland cancer. Locoregional control for patients with positive nodes increased from 40% to

69%. In most studies, an imbalance in prognostic factors is seen comparing surgery alone with combined therapy, favoring surgery alone. Despite this imbalance, locoregional control with combined surgery and postoperative radiotherapy is superior to surgery alone for patients with negative prognostic factors, irrespective of site (33,66,100,101,102). In the nationwide Dutch study, the relative risk for surgery alone, compared with combined treatment, was 9.7 for local recurrence and 2.3 for regional recurrence (100). In a study from Denmark, the relative risk of no radiotherapyversus radiotherapy was 4.7 for locoregional control (102). Postoperative radiotherapy is particularly effective if there are close and microscopic positive resection margins, enhancing local control from around 50% to 80% to 95% (33,41,77,100,102). Comparable results are noted for T3-T4 tumors and pathologically confirmed bone and perineural invasion (66,100). However, for a T1 or T2 tumor that was completely resected with no bone or perineural invasion, surgery alone will result in more than 90% 10-year local control rate, and radiotherapy is not indicated (100).

Treatment results also may depend on histopathologic status. However, after review, histologic type may change, even among experienced pathologists. In general, the best prognosis is shown for acinic cell and mucoepidemoid cancer, with a 15% risk of distant metastases after 10 years and a 10-year locoregional control rate of around 85%. Ten-year overall survival is around 80% and 65%, respectively (11,45,93,101). In one of three patients, postoperative radiotherapy is indicated (45,101). Squamous cell and undifferentiated tumors have been associatedwith a 10-year overall survival of 35% or less, caused by a high risk of distant metastases (35% and 50%, respectively) and locoregional recurrence (77,93,101). Postoperative radiotherapy is indicated in all cases to improve locoregional control. The intermediate-risk group consists of adenoid cystic cancer and cancer ex pleomorphic adenoma. Distant failure after 10 years is around 35% (39,92,101). Although the risk of nodal recurrence is low (5% to 10%), local recurrence is diagnosed more often (20% to 30%). A precipitous decrease in relapse-free survival is noted among 5 (around 70%), 10 (around 50%),

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and 15 years (around 45%) for patients with adenoid cystic carcinomas, which are well known for late recurrences (39,101). Significant improvement was reported in local control for adenoid cystic cancer with combined surgery and irradiation in several studies (33,39,81,89,96), regardless of site. Local tumor control rates with combined modality therapy for these tumors approach 85% to 90% at 10 years. Postoperative radiotherapy is also able to improve locoregional control rates with about 20% for high-grade tumors (62,81,96).

In the World Health Organization classification of 1991, among others, two new subtypes were described that are diagnosed relatively frequently. PLGA is situated solely in the palate.

Treatment consists of wide local excision. In a report by Castle et al. (17), treatment results of 164 tumors were analyzed, with 90% treated with surgery alone. Local control was 90%, with only few patients dying from PLGA. However, local failures may be seen even after long follow-up. In a series from Evans and Luna (29) of 40 patients with PLGA, local recurrence was seen in 43% of patients treated with surgery alone, mainly because of close and microscopic positive resection margins. No recurrence was seen in the nine patients treated with postoperative radiotherapy.

Salivary duct carcinoma is a very aggressive disease, and postoperative locoregional radiotherapy is indicated in all cases. Most patients die of disease, despite often successful locoregional combined therapy. Because of a high percentage of distant metastases, 5-year survival is only around 10% to 15% (42,52). The prognosis correlates with HER-2/neu receptor status; 3-year survival is 56% and 17% for (+)HER-2/neu and (+++)HER-2/neu, respectively (52).

Minor salivary gland tumors of the oral cavity have a more favorable prognosis than paranasal sinus tumors (maxillary and ethmoid sinus and nasal cavity) (38). Patients with hard palate lesions tend to be diagnosed when they have small asymptomatic lumps, which are easily detected on physical examination. On the other hand, paranasal sinus tumors usually do not cause symptoms until they are locally advanced. The surgical approach for these tumors is more difficult, with a greater chance for leaving behind residual disease, leading to high recurrence rates. A combined approach with surgery and postoperative irradiation is recommended.

Primary Radiotherapy

The poor results for salivary gland cancer with irradiation alone in several series have been attributed to the use of primary radiotherapy for patients with locally advanced lesions or distant metastases at presentation, who were essentially treated for palliation. Locoregional control rates after conventional photon or electron therapy are around 25% (49,60,66). For treatment with photons with curative intent, a clear dose-response relationship has been described (100). A dose of 66 to 70 Gy may result in 50% 5-year local control. Wang and Goodman (109) reported local control as high as 85% with accelerated hyperfractionated photon therapy. The follow-up was rather short, and the results have not been updated (109). The generally slow rate of regression of advanced salivary gland tumors have made them a logical target for alternative radiation therapy approaches, such as fast neutrons.

Neutron Therapy

Patients with inoperable primary or recurrent major or minor salivary glands were included in the RTOG-MRC randomized phase III clinical trial. Patients were randomized between 70 Gy for 7.5 weeks or 55 Gy for 4 weeks photon therapy and neutron

therapy. The study had to be stopped because of a statistically significant difference in 2-year locoregional control, after inclusion of only 32 patients. The 10-year locoregional control probability was 17% after photon therapy, and 56% after neutron therapy (60). However, survival was identical. Late morbidity was somewhat higher for neutron therapy. Douglas et al. (24) of the University of Washington have published results of 279 patients treated with neutrons. Almost all patients had evidence of gross residual disease. Major and minor salivary gland sites were equally distributed. Total dose, administered with neutrons, varied from 17.4 to 20.7 Gy. The 6-year locoregional control and cause-specific survival were 59% and 49%, respectively, conforming to the results of most studies. Locoregional control was only 19% for base of skull involvement and 67% for no involvement. Locoregional control was 72% for minor sites and 61% for major sites. The 6-year actuarial grade 3 and 4 toxicity was 10%. Less severe late morbidity may occur if neutron therapy is combined with photons. A study from Heidelberg for advanced, inoperable, recurrent, or incompletely resected adenoid cystic carcinoma compared results of treatment with neutrons, photons, or mixed beam (49). Severe late grade 3 and 4 toxicity was 19% with neutrons, compared to 10% with mixed beam and 4% with photon therapy. The 5-year local control was 75% for neutrons and 32% for mixed beams and photons; survival was identical.

In an effort to improve poor results for tumors invading the base of skull, several new techniques have been developed. A combination of neutron therapy with, after a 4-week split, a Gamma Knife stereotactic radiosurgical boost has been used for tumors invading the base of skull (26). Local control of eight patients treated with this technique looks promising; however, follow-up was only 2 years. Another option is a combination of photons (54 Gy) and carbon ions (18 Gy) radiotherapy (86). In a series of 16 patients with adenoid cystic cancer invading the base of skull, the 3-year local control was 65%, without late effects exceeding grade 2. Longer follow-up results of these new techniques are awaited.

In conclusion, neutron beam therapy seems to be the treatment of choice for unresectable, residual, or recurrent salivary gland tumors. Despite high locoregional control, survival is not improved and late toxicity is of concern.

Systemic Therapy

The rarity of these neoplasms and their localized nature provide limited opportunities for trials with chemotherapy. In a review by Lalami et al. (59), they stated that chemotherapy has to be considered as palliative treatment and should only be given for disease-related symptoms and rapidly progressive disease. Cisplatin as monotherapy shows a 20% response rate for locoregional disease and only 7% for distant failures, with a duration of 6 to 9 months. A combination of 5-fluorouacil, cyclophosphamide, cisplatin, and doxorubicin gives a response rate of 50% (59).

Carcinoma ex pleomorphic adenomas and salivary duct carcinomas express androgen receptors in a high frequency (69). There may be a possible role for antiandrogen therapy, combined with other treatment modalities. However, the efficacy of this treatment option for some salivary gland cancers still has to be proven.

Expression of vascular endothelial growth factor is seen frequently in salivary gland cancer and is related with poor prognosis. Overexpression of HER-2/neu also correlates with poor prognosis, and a great variety between histologic types has been demonstrated (59). In the future, the role of molecular-targeted therapy for these salivary gland cancers has to be established.

Sequelae of Treatment

The most notable complication of treatment of parotid malignancies is facial nerve paralysis, which is often caused by the initial or a repeated surgical procedure. However, various series have shown that facial nerve sacrifice is rarely necessary, unless the nerve is directly involved by tumor, particularly when postoperative irradiation is given (33,77,91). When facial nerve sacrifice is required, facial nerve grafting and postoperative radiation therapy achieve comparable facial nerve function compared with unirradiated graft despite more negative prognostic factors (14). Other postoperative sequelae, such as salivary fistulae and neuromas of the greater auricular nerve, are sometimes seen. Frey's syndrome (i.e., gustatory sweating) may occur in a few patients after parotid surgery, but it is rarely bothersome (58).

Partial xerostomia after irradiation of the parotid gland is frequently observed and may be permanent. Trismus may result from radiation-induced fibrosis of the temporomandibular joint or the masseter muscles. It usually occurs when there is extensive tumor infiltration of the masseter muscle and high doses are given. Data on dose-response relationship for radiation-induced hearing impairments are sparse. In a study by Chen et al. (18), with 21 patients treated for malignant parotid tumors, a significant hearing loss was noted after a cochlear dose of ≥60 Gy in 60%, and in no patient after a dose <60 Gy. Conductive hearing loss was caused by serous effusion in the middle ear and/or obstruction of the tuba Eustachius. In general, a dose as low as possible (<30 Gy) should be attempted (53).

Garden et al. (38) reported complications of irradiation in 51 of 160 patients receiving postoperative irradiation for minor salivary gland tumors. The most common complication was decreased hearing in 26 patients, 20 of whom had myringotomies or myringotomy tubes placed for serous otitis media. Bone necrosis or exposure was observed in several patients; however, this complication has been seen infrequently during the past decade with improved radiation therapy techniques and treatment of multiple, as opposed to single, fields per day. Complications to the eyes or optic pathways were most common in patients with paranasal sinus primary tumors. At least six cases of contralateral optic atrophy occurred. Other eye complications included dry eye syndrome, nasolacrimal duct obstruction, cataract, retinopathy, and perforated globe. To reduce the incidence of bilateral blindness, the dose to the optic chiasm and contralateral optic nerve is limited to 54 Gy. In patients with extensive tumor involvement of the orbit, it may be preferable to remove the eye surgically rather than to subject the entire orbit to high doses. Radiation-induced injury to the visual pathway is dose-dependent. None of the patients receiving a dose of less than 50 Gy develop optic neuropathy or chiasm injury, whereas the 10-year actuarial incidences of optic nerve chiasm injury is 5% and 30% for patients receiving 50 to 60 Gy and 61 to 78 Gy, respectively (54).

Radiotherapy of tumors of the pharynx, and less frequently the oral cavity, may result in permanent complaints of xerostomia. The mean dose to the parotid glands that relates to 1-year xerostomia may range from 26 Gy (27) to 39 Gy (82). This serious late complication may be significantly reduced by the use of IMRT (51,99). For those patients with a dose to both parotid glands that exceeds at least 39 Gy, amifostine administration during head and neck radiotherapy will reduce the severity and duration of xerostomia 2 years after radiotherapy (110), without compromising locoregional control.

Treatment of Recurrence

Retreatment usually involves additional surgery, if feasible, and postoperative irradiation in previously unirradiated patients (Fig. 40.13). In the retreatment of parotid neoplasms,

preserving facial nerve function and obtaining local control are more difficult than for the initial tumor. Therapy consisting of surgery with postoperative irradiation has demonstrated enhanced local control, and facial nerve sacrifice may be necessary less often if this combination is used. In certain histologic subtypes (e.g., adenoid cystic carcinoma), retreatment of locally recurrent disease yields prolonged survival (89). Aggressive local therapy for recurrent disease is indicated if the probability of long-term survival is high.

Chemotherapy also has been used for recurrent disease. Polychemotherapy for recurrent high-grade disease may result in around 45% response rate, with a median duration of 7.5 months (1). However, in view of its significant toxicity and modest response rates in a population that may have recurrent yet indolent progressive disease, trials of aggressive cytotoxic therapy are recommended only on carefully drafted protocols. In the future, molecular target agents may be tested in selected recurrent salivary gland cancers.