Sinonasal Cancer

Nasal Vestibule

The nasal vestibules are the two entry points into the nasal cavity. Each is a triangle-shaped space situated in front of the limen nasi and defined laterally by the lateral crus and alar fibrofatty tissue, medially by the medial crus of the alar cartilage and the nasal septum and the distal end of the cartilaginous septum, and columella (see Figs. 42.2 and 42.3 ). The nasal vestibule is covered by skin and, therefore, lesions at this location are essentially squamous cell skin cancers, but may occasionally be basal cell carcinoma, sebaceous carcinoma, melanoma, or non-Hodgkin's lymphoma. Nasal vestibule cancers are analogous to cancers of the anal margin. Human papilloma virus has been implicated in the development of nasal septal cancers.

Cancers of the nasal vestibule are said to arise preferentially on the medial wall, which is the nasal septum. Nasal vestibule carcinomas can spread by invasion of the upper lip, gingiva-labial sulcus, premaxilla, or nasal cavity. 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. The buccinators nodes can be found on the buccinator muscle or in the fat of the buccinator space ( Fig. 42.2 ) .

The buccinators nodes are divided into anterior or posterior buccinator, depending on their relationship to the facial vein. The mandibular nodes include the supramaxillary nodes, the supramandibular nodes, and the inframandibular nodes and lie along the external surface of the mandible adjacent to the facial artery and anterior to the masseter muscle. Large lesions extending across the midline may spread to the contralateral facial or submandibular nodes. The average incidence of nodal metastasis at diagnosis is approximately 5%. Without elective lymphatic treatment, about 15% of patients develop nodal relapse. In the intensity-modulated radiation (IMRT) era, when parotid sparing is de rigour , the 15% incidence of nodal relapse makes consideration of elective nodal irradiation mandatory for patients with locally advanced disease. Hematogenous metastases are rare in nasal vestibule carcinomas.

Nasal Cavity and Ethmoid Air Cells

Nasal cavity and ethmoid sinus tumors share a common staging system. The nasal cavity proper (nasal fossa), which excludes the nasal vestibule, begins at the limen nasi anteriorly and ends at the choana posteriorly. It extends from the hard palate inferiorly to the cribriform plate superiorly. The lateral walls consist of three thin bony structures, the superior, middle, and inferior turbinates (or concha), that project inferomedially into the nasal cavity ( Fig. 42.4 ).The middle turbinate attaches to the cribriform plate superiorly and then posteriorly and laterally to the lamina papyracea.

The region inferior to each turbinate is defined as the superior, middle, and inferior meati (see Fig. 42.4 and eFig. 42.3 ). The superior meatus receives drainage from the posterior ethmoid air cells and the sphenoid sinus at the sphenoethmoidal recess. The middle meatus is a particularly important site of drainage, receiving drainage from the anterior ethmoids, the frontal sinus, and the maxilla. The anterior ethmoid air cells drain into the ethmoid bulla at the superior aspect of the osteomeatal complex; the frontal sinus drains into the middle meatus at the anterior portion of the osteomeatal complex, whereas the maxillary sinus dumps its content past the infundibulum (a valve at the superior medial aspect of the maxilla) into the middle meatus by way of the maxillary ostium at the inferior osteomeatal complex (see red arrow on eFig. 42.4 ). Of course, the inferior meatus receives drainage from each nasolacrimal duct ( Table 42.3 ).

The septum divides the nasal cavity into right and left halves (see Fig. 42.3 ). The olfactory nerves penetrate the cribriform plate and innervate the roof of the nasal cavity, superior nasal turbinate, and the upper third of the septum. This portion of the nasal cavity is referred to as the olfactory region. The remaining part of the cavity, the respiratory region, contains orifices connecting the nasal cavity with the paranasal sinuses.

The ethmoid sinuses comprise several small cavities, called ethmoid air cells, within the ethmoidal labyrinth located below the anterior cranial fossa and between the nasal cavity and the orbit ( eFig. 42.5 ) . They are separated from the orbital cavity by a thin, porous bone called the lamina papyracea and from the anterior cranial fossa by a portion of the frontal bone, the fovea ethmoidalis.

Neoplasms originating in the respiratory region of the nasal cavity and ethmoid cells are squamous cell carcinoma, adenocarcinoma, and adenoid cystic carcinoma. Carcinoma may arise from inverted papilloma.

The pattern of contiguous spread of carcinomas varies with the location of the primary lesion. Tumors arising in the upper nasal cavity and ethmoid air cells extend to the orbit through the lamina papyracea and to the anterior cranial fossa via the cribriform plate or they grow through the nasal bone to the subcutaneous tissue and skin. Lateral wall primaries invade the maxillary antrum, ethmoid airs cells, orbit, pterygopalatine fossa, and nasopharynx. Primaries of the floor and lower septum may invade the palate and maxillary antrum. Spreading may also occur through perineural spaces, especially when the histology is adenoid cystic cancer ( eFig. 42.6 ).

Lymphatic spread of respiratory region primaries is variable and involvement of level I is common in those patients who fail regionally. Recommendations include neck treatment for patients with T3 or T4 paranasal sinus squamous cell cancers as well as sinonasal undifferentiated carcinomas (SNUCs).

Turning first to nasal cavity, where approximately 50% of the patients have a squamous cell histology, a review of 23 studies with a median follow-up of 4.4 years found the weighted average regional recurrence rate for squamous cell cancers of the nasal cavity to be 18.1%. At least some patients from 7 of the 23 studies received prophylactic cervical nodal irradiation, which significantly lowered the rate of neck failure.

The review of the Istituto Nazionale per lo Studio e la Cura dei Tumori of Milan experience from 1968 to 2003 identified 305 consecutive tumors of the ethmoid sinus. There was a striking male predominance, 70.8% versus 29.2%. Intestinal type adenocarcinoma was the most frequent histology, 50.2%, with only 10.8% of patients with ethmoid sinus cancer having squamous cell cancer. Other series disagree (see later in this chapter). The strong male predominance was confirmed in a 202 person study of European patients with adenocarcinomas of the ethmoid sinus. Only 1.6% of 305 patients with ethmoid sinus cancer presented with adenopathy and with a median follow-up of 109 months, the cumulative incidence of lymphatic recurrence was 4.3%. It is important to note that most neck recurrences were accompanied by recurrence of the primary tumor. The 5-year cumulative incidence of metastases was just 3.6%.

The olfactory region is located at the roof of the nasal cavity. It represents a narrow strip demarcated by the lamina cribrosa and the adjoining septum and lateral walls. The olfactory region is the site of origin of esthesioneuroblastoma and, occasionally, adenocarcinomas.

Esthesioneuroblastoma is a tumor of neural crest origin first reported by Berger et al. in 1924 as esthesioneuroepithelioma olfactif. It has been given a variety of other names, including olfactory neuroblastoma and esthesioneurocytoma. Esthesioneuroblastoma constitutes approximately 3% of all intranasal neoplasms. About 250 cases were reported in the literature between 1924 and 1990. A typical histologic feature of esthesioneuroblastoma is that of a tumor composed of round, oval, or fusiform cells containing neurofibrils with pseudorosette formation and diffusely increased microvascularity. Perivascular palisading of cells can be observed in the absence of pseudorosette formation. Turri-Zanoni et al. have described a clinicopathological spectrum connecting esthesioneuroblastoma and sinonasal neuroendocrine cancers and stressed the importance of using a positive CK8/18 despite negative CKAE1/AE3 to distinguish the neuroendocrine neoplasms from esthesioneuroblastomas.

Neuroendocrine neoplasms have inferior overall and disease-free survival when compared with esthesioneuroblastomas ( eFig. 42.7 ), but may benefit from induction chemotherapy ( eFig. 42.8 ).

By light microscopy, esthesioneuroblastoma may be mistaken for any other “small round-cell tumor”—a group of aggressive malignant tumors composed of relatively small and monotonous undifferentiated blue staining cells. These include Ewing sarcoma, peripheral neuroepithelioma (also referred to as primitive neuroectodermal tumor or extraskeletal Ewing sarcoma), peripheral neuroblastoma (“classic-type”), rhabdomyosarcoma, desmoplastic small round-cell tumor, lymphoma, leukemia, small-cell osteosarcoma, small-cell carcinoma (either undifferentiated or neuroendocrine), olfactory neuroblastoma, cutaneous neuroendocrine carcinoma (Merkel-cell carcinoma), small-cell melanoma, and mesenchymal chondrosarcoma. Their clinical presentations often overlap, but clinicopathologic features and immunohistochemistry may help in differentiation.

The route of contiguous spread of esthesioneuroblastomas is similar to that of ethmoid carcinomas. Multiple and late local and regional recurrences are the rule. Eventual development of neck disease has been reported in 21 of 110 patients and in 20.2% of 678 patients, with 61.7% of the cervical disease occurring more than six months after the diagnosis.

Maxillary Sinus

Maxillary sinuses, the largest of the paranasal sinuses, are pyramid-shaped cavities located in the maxillae. The base of the maxillary sinus forms the inferior part of the lateral wall of the nasal cavity. The roof of the maxillary sinus is formed by the floor of the orbit, which contains the infraorbital canal, and the floor is composed of the alveolar process. The apex extends toward, and frequently into, the zygomatic bone. Ohngren's line is a theoretical line passing from the medial canthus of the eye to the angle of the mandible and divides the maxillary sinus cancers into a suprastructure and infrastructure. Tumors superior to this arbitrary plane are in close proximity to and may invade the orbit and middle cranial fossa earlier in the course of disease and thus have a worse prognosis. Also of importance when understanding the anatomy of the maxillary sinus is the pterygopalatine fossa. The pterygopalantine fossa, also known as the sphenopalatine fossa, can be thought of as a box, with its anterior wall being the posterior wall of the maxillary sinus. The posterior wall is the pterygoid plates and inferior aspect of the sphenoid bone; the roof is the inferior orbital fissure. The floor is the palantine canal and contains the greater palantine nerve. Medially it is defined by the perpendicular plane of the palatine bone. The pterygopalatine fossa contains the maxillary nerve (V2), which enters from the brain via the foramen rotundum, as well as the pteryogoplatine ganglion and the distal maxillary artery, which enters via the pterygomaxillary fissure. The pteryogopalatine ganglion is the largest head and neck parasympathetic ganglion and has sensory, motor, and sympathetic function.

Sixty-two percent of maxillary sinus cancers are squamous cell carcinomas. Other histologic types and survivals are shown in Table 42.4 .

The pattern of spread of maxillary sinus cancer varies with the site of origin. Neoplasms of the suprastructure tend to extend into the nasal cavity, nasopharynx, ethmoid cells, inferior or medial wall of the orbit, orbital contents, pterygopalatine fossa, masticator space, infratemporal fossa, base of the skull, parasellar region and cavernous sinus, and middle cranial fossa. Tumors of the infrastructure extend to the palate, alveolar process, gingivobuccal sulcus, soft tissue of the cheek, nasal cavity, masseter muscle, pterygopalatine space, and pterygoid fossa. It is sometimes difficult to differentiate a primary maxillary cancer from a primary oral cavity cancer extending into the maxillary sinus from the upper alveolus and hard palate.

Overall, the incidence of clinical lymphadenopathy is relatively uncommon at diagnosis, but because regional recurrence is common, the presumption is that subclinical nodal disease exists at presentation. Cantù et al. reported that 8.3% of 399 patients presented with lymphadenopathy and during follow-up (median 109 months) 12.5% developed regional recurrence. Squamous cell primary cancers of the maxilla had a 10.3% incidence of nodal disease at presentation, with a 36.4% lymph node recurrence rate in N+ patients. The cumulative incidence of neck recurrence for patients with squamous cell cancer of the maxilla was 20.7%. Le et al. has published the location of nodal presentation and failure and found that level IB, II, V, and the preauricular area can be involved ipsilaterally, and levels II contralaterally.

Sinonasal Undifferentiated Carcinoma

Sinonasal undifferentiated carcinoma has been identified by the World Health Organization as a distinct sinonasal neoplasm that should be differentiated from ethesioneuroblastoma and other cancers. There is a male predominance and tumors typically are aggressive, presenting with locally extensive disease. Etiology is unknown. Immunohistochemical studies are noncontributory and stains for epithelial mucin are negative. The nuclear-to-cytoplasmic ratio is high with a very high mitotic rate. In 2005 there were fewer than 100 cases of SNUC described; by 2008 approximately 200 cases were described and a review from 2009 as well as anecdotal experience suggested that the diagnosis is becoming more common. Scanty evidence (n = 17) reported that SNUC is one of the few ethmoid sinus cancers with a 25.5% rate of regional failure. A 13% rate of regional failure in 26 SNUCs from the maxilla was reported. Mendenhall's review of the literature found 10% to 30% of patients with SNUC present with clinically positive adenopathy and the cure rates varied from 20% to 50%.

Nasal Vestibule

Small carcinomas of the nasal vestibule usually present as asymptomatic plaques or nodules, often with crusting and scabbing. The septum is the most common location. Advanced lesions may extend to adjacent structures, such as upper nasal septum, upper lip, infranasal depression (philtrum), skin of nose, nasolabial fold, hard palate, buccogingival sulcus, and so forth. Deep muscle and bone and nerve involvement may cause pain accompanied by bleeding or ulceration. Large ulcerated lesions may become infected, leading to severe tenderness that hinders complete clinical assessment. The contiguous spread is best assessed by bimanual palpation and examination through a nasal speculum or fiberoptic endoscope after mucosal decongestion and topical anesthesia. Early buccinator and submandibular nodal involvement may be detected by bimanual palpation or by imaging. Staging of nasal vestibule carcinoma is by the TNM classification system for the skin. However, other staging systems have been utilized in reporting data.

Nasal Cavity and Ethmoid Air Cells

Esthesioneuroblastoma

The natural history of esthesioneuroblastomas is long and multiple recurrences are the rule. Surveillance, Epidemiology and End Results (SEER) analysis of 311 patients found the age distribution to be unimodal with the mean age being 53. SEER analysis described the primary site as the nasal cavity in over three-quarters of the cases and 12.3% presented with nodal involvement.

The most common presenting symptoms are nasal obstruction and epistaxis. Anosmia can 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), and manifestation of inappropriate antidiuretic hormone secretion. Most present in the nasal cavity ( eFig. 42.9 ).

Physical evaluation and recommended staging workup procedures for esthesioneuroblastoma are similar to those for nasal fossa tumors. A commonly used staging system, proposed by Kadish et al., and modified by Morita et al. is as follows:

• Stage A: disease confined to the nasal cavity

• Stage B: disease confined to the nasal cavity and one or more paranasal sinuses

• Stage C: disease extending beyond the nasal cavity and the paranasal sinuses, including involvement of the orbit, the base of the skull or intracranial cavity

• Stage D: cervical lymph node involvement or distant metastases

In an analysis from the National Cancer Database, the Kadish stage distribution of 883 patients with esthesioneuroblastoma was 22% stage A, 13% stage B, 56% stage C, and 9% stage D.

Maxillary Sinus

Because of their relatively silent presentations, maxillary cancers are often diagnosed late. Of the 73 patients referred to MDACC for treatment between 1969 and 1985, for example, symptoms and signs related to extension to the premaxillary region (facial swelling, pain, or paresthesia of the cheek) occurred in 26 (36%). Symptoms caused by tumor spread to the nasal cavity (e.g., epistaxis, nasal discharge or obstruction) or oral cavity (e.g., ill-fitting denture, alveolar or palatal mass, or unhealed tooth socket after extraction) occurred in 20 (27%) and 19 (26%), respectively. Five patients (7%) presented with symptoms and signs of orbital invasion, such as proptosis, diplopia, impaired vision, or orbital pain.

Physical examination should include assessment of the oral and nasal cavities, palpation of the cheek, evaluation of the eye movement and function, and assessment of the trigeminal nerve, particularly the branches of the maxillary division (infraorbital, anterior superior alveolar, posterior superior alveolar, and greater palatine nerves). Numbness of the incisor teeth and upper lip, however, can result from biopsy through a Caldwell-Luc procedure. CT and/or MRI with appropriate contrast is essential to determine the disease extent and invasion of adjacent structures (e.g., orbital cavity, infratemporal, pterygopalatine, and anterior cranial fossae).

Nasal Vestibule

Nasal vestibule cancers are skin cancers that are in a cosmetically important location. Radiotherapy is generally preferred for carcinoma of the nasal vestibule because of better cosmetic outcome, but if local excision of a medial tumor of the nasal septum can be performed with clear margins and no cosmetic deformity, that treatment may also be appropriate. Surgery can yield a high control rate with excellent cosmetic results in selected small, superficial lesions. Depending on the location and size of the primary lesion, radiation treatment can be accomplished by external beam irradiation (EBRT), brachytherapy, or a combination of both. Cartilage invasion per se is not a contraindication for radiation therapy because the risk of necrosis is low with fractionated irradiation. Rare cases of large primary tumors with extensive tissue destruction and distortion are best managed by resection in combination with preoperative or postoperative radiotherapy. Experienced prosthodontists can design custom-made nasal prostheses for large defects. Smaller defects can be reconstructed with a rotational or advancement flap.

Because of disagreement regarding the applicability of the AJCC staging system, some authors use the Wang staging system and some use the AJCC skin cancer staging system, which further complicates comparison of results in a relatively rare tumor. Additionally, there are parochial concerns about whether nasal vestibule is a surgical disease or not. Eloquent editorials aside, there is a dearth of randomized data, and endpoints such as cosmetic results are difficult to quantify.

The University of Florida, Gainesville reports that 32 of 34 patients with disease 5 cm or smaller who were treated with definitive radiation were locally controlled ( Table 42.5 ). Generally, radiation doses were high (65 Gy to 75 Gy), but techniques varied between definitive EBRT, a combination of brachytherapy and EBRT, and brachytherapy alone. The authors conclude that definitive radiation gives both good local control and cosmesis for early tumors, but tumors involving bone that are more than 4 cm should be treated with a combination of surgery and radiation. The importance of both size and bone invasion is seen in Table 42.6 .

Elective nodal irradiation (ENI) was only recommended for tumors involving bone that are more than 4 cm in size but the 5 year neck control and ultimate neck control were 87% and 97% suggesting good follow-up and 7 neck salvages in 9 patients. The control rates of the N0 neck when the primary tumor was continuously controlled appear in Table 42.7 .

TABLE 42.7

Initial Control of the N0 Neck When the Primary Tumor Was Controlled, University of Florida

Treatment	Size	Without ENI a	ENI
RT alone	≤ 5 cm	29/31 (94%)	nd
	T4-”Extradermal”	11/15 (73%)	8/8
	≤ 5 cm but recurrent	6/6	1/1
	T4-”Extradermal” r		1/1
	Total	47/54 (87%)	10/10

a ENI, elective node irradiation; nd, no data; RT, radiotherapy.

The DAHANCA retrospective review noted that 54 Gy in 18 fractions was more effective than 62 Gy to 66 Gy in 31 to 33 fractions for T1 lesions. However, complications were not discussed.

An overall local control of 93% was found on analysis of irradiation of 1676 carcinomas of the skin of the nose and nasal vestibule performed by the Groupe Europen de Curietherapie in France. 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%), and on whether a tumor was recurrent or new (88% vs. 95%). Local control was independent of histology for tumors less than 4 cm, but for those larger than 4 cm, basal cell carcinomas were more frequently controlled than squamous cell carcinomas. There were few complications (necrosis, 2%). The local control rate with surgery was approximately 90%.

Other series conclude that more advanced lesions are better handled by combined modality treatment.

Table 42.8 summarizes the results of six series of patients treated by radiotherapy. Patients received brachytherapy, EBRT or a combination. On average, about 90% of nasal vestibule cancers smaller than 2 cm can be cured with brachytherapy or EBRT. Surgery offers equivalent results. The University of Florida showed 94% control for lesions less than 5 cm. Others have shown 70% to 80% local control with radiation alone with surgical salvage bringing the ultimate local control to 94%. Occult nodal spread is extremely rare in lesions smaller than 2 cm, but can be as high as about 40% in larger primary tumors. Once again surgical salvage of neck failures is high. The University of Florida has documented a relatively high rate of radiation salvage for surgical failures. Finally, complications from radiation therapy alone are relatively mild. In 71 patients treated with definitive radiation at the University of Florida, there was a 21% incidence of complications with the majority being soft-tissue necrosis and no complication required hospitalization or surgical intervention. Perhaps counter-intuitively, 3 of 8 patients treated with surgery and radiation developed severe complications.

Nasal Cavity and Ethmoid Air Cells