INTRODUCTION — There are a number of different malignant neoplasms that arise in the nasal cavity and paranasal sinuses, the most common of which are squamous cell carcinoma and variants of adenocarcinoma, followed by neuroendocrine tumors and mucosal melanoma.
This topic discusses malignant tumors of epithelial origin arising in the nasal cavity and paranasal sinuses. Lymphoreticular malignancies (including natural killer [NK]/T cell lymphoma and plasmacytoma), sarcomas, and benign neoplasms, such as inverted papilloma, are addressed elsewhere. This review will address the pertinent anatomy, histological variants, initial evaluation, staging, treatment strategies, and outcomes for nasal cavity cancers.
Related topics include:
●(See "Cancer of the nasal vestibule".)
●(See "Paranasal sinus cancer".)
●(See "Olfactory neuroblastoma (esthesioneuroblastoma)".)
EPIDEMIOLOGY AND RISK FACTORS — Primary malignant tumors of the nasal cavity and paranasal sinuses are rare, accounting for less than 3 percent of tumors of the upper aerodigestive tract and less than 0.5 percent of all cancers [1]. The overall incidence and epidemiology of these tumors are illustrated by an analysis of the Surveillance, Epidemiology, and End Results (SEER) registry from 1973 to 2006, which identified 6739 nonlymphoreticular malignancies arising in the nasal cavity and accessory sinuses [1]:
●The overall incidence rate was 0.56 cases per 100,000 population per year [1].
●The nasal cavity was the most common primary site, followed by the maxillary sinus (44 and 36 percent, respectively).
●Nasal cavity tumors were more common in males than females, with a 1.8:1 ratio.
●Most patients were diagnosed in the sixth decade of life or later, and the racial distribution was similar to that of the general population.
Risk factors associated with nasal cavity tumors include:
●Tobacco smoke, which is a major risk factor for squamous cell carcinoma [2,3].
●Occupational and chronic exposures to inhaled wood dusts, glues, and adhesives are associated with sinonasal adenocarcinoma [4-6]. Persons with occupational exposure to wood dusts have a 500- to 900-fold increased risk of developing sinonasal adenocarcinoma compared with the general population [7].
●A National Cancer Database study identified human papillomavirus (HPV) infection as a significant risk factor in patients with sinonasal squamous cell carcinoma where 32 percent of cases were positive [8]. In this study, HPV positivity was associated with improved five-year overall survival compared with HPV negative tumors (68.1 versus 51.5 percent) [8]. Although HPV positivity in sinonasal cancers confers the same favorable prognosis associated with HPV-associated oropharyngeal squamous cell carcinoma, our understanding of the significance of HPV positivity in sinonasal cancers is evolving.
ANATOMY — An understanding of the anatomy of the nasal cavity and paranasal sinuses is essential for the proper evaluation, staging, and treatment of patients with a nasal cavity tumor (figure 1).
Proximally, the nasal cavity is separated from the nasal vestibule (the hair-bearing portion of the nose) by the limen nasi and posteriorly from the nasopharynx by the choanae; it is bounded by the hard palate inferiorly and by the skull base (frontal bone, cribriform plate of the ethmoid bone, and sphenoid bone) superiorly. The nasal cavity is separated into halves by the nasal septum and is bounded laterally by the maxillary and ethmoid sinuses.
Anatomic communication between the nasal cavity and adjacent structures can serve as a conduit for tumor spread:
●The choanae connect the nasal cavity to the nasopharynx.
●Additional communications are located in the lateral walls of the nasal cavity deep to three paired turbinates (or concha).
•The nasolacrimal duct courses through the maxilla and terminates in the inferior meatus lateral to the inferior turbinate.
•The middle meatus is lateral to the middle turbinate and serves as the terminus for outflow from the frontal, maxillary, and anterior ethmoid sinuses. From anterior to posterior, the uncinate process of the ethmoid bone and the ethmoid bulla form the semilunar hiatus, which contains the infundibulum that leads to the frontal recess, frontal sinus, and the openings to the anterior ethmoid air cells. The ostia of the maxillary sinus lie posteriorly.
•The sphenopalatine foramen is the most posterior opening in the middle meatus and forms the communication between the nasal cavity, and the pterygopalatine fossa and infratemporal fossa.
•The ostial openings to the posterior ethmoid air cells are in the superior meatus deep to the superior turbinate.
The proximity of the nasal cavity and paranasal sinuses to critical skull base structures, including the brain, eyes, cranial nerves, and visual pathways, makes local management of nasal cavity tumors challenging. Most nasal cavity tumors are diagnosed at a locally advanced stage and cross tissue boundaries, including the paranasal sinuses, orbits, and skull base structures. At least 50 percent of patients have involvement of more than one anatomic subsite. Orbital invasion was identified in 11 percent of a series of 876 patients with sinonasal malignancies [9]. Cranial nerves can serve as conduits for tumor spread in as many as one-third of patients [10].
HISTOLOGY — Squamous cell carcinoma is the most common histology of nasal cavity tumors, but nonsquamous histologies are more likely in the nasal cavity than in the mucosa of other head and neck sites. These include adenocarcinoma and its variants (mucoepidermoid carcinoma, adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, adenocarcinoma not otherwise specified, and acinic cell carcinoma), neuroendocrine tumors (olfactory neuroblastoma, also referred to as esthesioneuroblastoma; sinonasal undifferentiated carcinoma; and small cell carcinoma), and mucosal melanoma. (See "Pathology of head and neck neoplasms".)
Several distinct histologic entities have been described, including nuclear protein testis (NUT) midline carcinoma and SMARCB1 (INI-1)-deficient sinonasal carcinoma [11], both of which require molecular analysis for confirmation, and have likely historically been characterized as poorly differentiated squamous cell carcinoma. However, unlike squamous cell carcinoma of the sinonasal region, these entities tend to present with very advanced disease and have a much less favorable prognosis.
Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma, a cancer with distinct features of both surface-derived and salivary gland carcinoma, has been reclassified based on a strong association with high-risk HPV (non-16/18 subtype). In one observational series of these rare tumors, 67 percent of tumors were positive for HPV 33 [12]. In addition to this subtype, a large fraction of sinonasal squamous cell carcinoma is HPV positive, and more frequently reflect non-HPV 16 types. Although HPV positivity is a positive prognostic indicator in the oropharynx, the biology appears to be different in the sinonasal cavities, and prognostic value in this site has not been quantified.
CLINICAL PRESENTATION — Most patients with nasal cavity carcinoma present with symptoms of locally advanced disease; these include nasal obstruction and epistaxis (71 and 42 percent, respectively) [4]. In more advanced disease, presenting symptoms can be due to involvement of adjacent structures, such as facial swelling/pain, proptosis, diplopia, cranial nerve dysfunction, seizure, and nodal masses.
INITIAL EVALUATION
History and physical examination — Patients with nasal cavity tumors require a thorough history and physical examination, along with a complete head and neck examination including nasal endoscopy. This should include assessment of cranial nerves, ophthalmologic function, audiometry, and neck exams.
Biopsy — An adequate biopsy specimen for histopathology is required to accurately diagnose and classify nasal cavity tumors. Tumor biopsies are usually obtained endoscopically with sinus surgery instruments. In some cases, a fine needle aspirate biopsy may be performed.
Imaging — Imaging studies, including both computed tomography (CT) and magnetic resonance imaging (MRI), are important to evaluate the extent of disease (image 1).
The imaging findings with early stage sinonasal tumors are similar to those of rhinosinusitis and may easily be confused with benign pathology. However, unilateral sinus opacification and bone destruction are important signs that may indicate the presence of malignancy [13,14]. Imaging of sinonasal tumors requires intravenous contrast to delineate the extent of tumor involvement, unlike imaging for benign rhinosinusitis. CT and MRI provide complementary information about the extent of local-regional disease:
●CT is the best modality to evaluate bony changes, such as cortical bone erosion, destruction, remodeling, sclerosis, and reactive thickening.
●MRI is used to characterize the soft tissue components of the tumor and to evaluate the extent of tumor invasion beyond the bony structures, especially the orbital, intracranial, and perineural extension of disease [15]. T2-weighted images are especially useful in distinguishing benign opacities, such as fluid collections, from tumors. Fat suppression is critical in the evaluation of perineural disease and orbital invasion.
●Once the diagnosis of cancer has been established, neck imaging is indicated to evaluate for lymph node metastasis, with careful attention to the retropharyngeal lymph nodes as well as level 1b and 2a cervical lymph node stations.
●The role of 18-FDG positron emission tomography (PET)-CT imaging is less clear for nasal cavity cancers, although it may be helpful in detecting retropharyngeal or cervical lymph node involvement. PET-CT may also be particularly useful in detecting distant metastases in patients with olfactory neuroblastoma or mucosal melanoma. As an example, in a series of 28 patients undergoing staging evaluation for olfactory neuroblastoma, the addition of PET-CT to standard imaging changed the disease stage or altered the clinical management of 39 percent of patients, mostly due to upstaging by detecting a cervical lymph node or distant metastases [16]. In the follow-up of patients previously treated for olfactory neuroblastoma, PET-CT detected 75 percent of recurrences. The remaining 25 percent of patients were PET-CT negative, and recurrences were detected on endoscopy and/or MRI. The authors concluded that PET-CT alone is helpful in follow-up but does not negate the need for MRI and endoscopic evaluation for adequate detection of recurrences [17].
The use of gallium Ga-68 DOTATATE PET-CT in patients with olfactory neuroblastoma is discussed separately. (See "Olfactory neuroblastoma (esthesioneuroblastoma)", section on 'Imaging studies'.)
STAGING — Nasal cavity tumors are staged according to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) system (table 1) [18]. Staging is based upon both the visual assessment of the extent of disease and imaging studies. In the eighth edition of the AJCC staging system, the only change in the staging of nasal cavity tumors includes the reclassification of patients with clinical or pathological extranodal extension (ENE) as N3b, which is uncommon in nasal cavity tumors. Of note, this change is only applicable to patients with non-human papillomavirus (HPV) related cancers.
TREATMENT OF LOCOREGIONAL DISEASE — For patients with early-stage or locoregionally advanced disease, aggressive management of the primary tumor is critical since local disease and extension into adjacent structures are the major causes of morbidity and mortality. Regional lymph node disease and distant metastases are primarily seen with late presentation, very aggressive histologic variants, or progressive disease. A multidisciplinary team that includes head and neck surgeons, neurosurgeons with skull base expertise, medical oncologists, and radiation oncologists should participate in the discussion of the initial treatment strategy.
Treatment recommendations for patients with locoregional nasal cavity tumors are based on observational case series, since data for randomized trials comparing treatment alternatives are limited. Furthermore, many retrospective studies have combined nasal cavity tumors with paranasal sinus tumors, making it difficult to draw conclusions that are specific to nasal cavity cancers.
Approach — For patients without sinonasal undifferentiated carcinoma or small cell carcinoma histologies, we suggest the following approach:
●For patients with resectable disease, the standard treatment is surgery followed by postoperative RT [19-21]. We prefer this approach rather than either surgery or RT alone because there is a significant risk of local recurrence with surgery alone, and the proximity of the brain and eye make treatment with high doses of single agent RT problematic. (See 'Surgery' below and 'Radiation therapy' below.)
•Although preoperative RT has been used to minimize tumor bulk and limit the extent of resection, postoperative RT is generally preferred to minimize the risk of wound complications following surgery [22].
•Surgery alone is a reasonable option for some carefully selected patients with T1N0 tumors; however, such early-stage disease is rare.
●For patients with unresectable disease, we treat with combined modality therapy including RT and chemotherapy.
•For patients with unresectable tumors and good performance status, we suggest cisplatin-based chemotherapy concurrent with RT, extrapolating from studies assessing squamous cell carcinoma of other head and neck sites. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)
•The addition of induction chemotherapy prior to concurrent chemoradiation (CRT) is increasingly used for unresectable tumors. Further randomized trials assessing the role of induction chemotherapy in sinonasal squamous cell carcinoma are needed.
Despite limited data on whether this approach is effective in sinonasal tumors with squamous histology, we offer induction chemotherapy prior to definitive CRT in select patients with squamous histologies, in whom significant tumor reduction with chemotherapy would allow for more conformal radiation treatment volumes, with less potential for morbidity (eg, to structures such as the eye, brain, or swallowing apparatus). The approach to induction chemotherapy for these patients is similar to those with squamous cell carcinoma of other head and neck sites and is discussed separately. One particular challenge with this approach in sinonasal cancers is determining the extent to which initial tumor-related findings in the central nervous system, skull base, and orbit that regress with induction chemotherapy need to be addressed with radiotherapy or surgery. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Induction chemotherapy'.)
●For older adults with severe comorbid conditions and poor performance status, we offer treatments with palliative intent, which may include debulking surgery, RT, and systemic chemotherapy in addition to medical management of symptoms and psychosocial support. (See 'Treatment of metastatic disease' below.)
The treatment approach to patients with more aggressive neuroendocrine histologies (eg, sinonasal undifferentiated carcinoma and small cell carcinoma), which incorporates the use of induction chemotherapy, is discussed below. (See 'Sinonasal undifferentiated and small cell carcinoma' below.)
Surgery — The goal of surgery is the complete resection of all visible disease while preserving function and cosmesis. Widely negative margins are not usually achievable in most cases given the anatomic constraints of the brain and eyes. Surgical teams should include specialists in otolaryngology-head and neck surgery and neurosurgery with experience in sinonasal and skull base surgery. Additionally, surgical expertise in microvascular free tissue transfer and skull base reconstruction may be required to restore form and function to the face and skull base.
Surgical approaches include traditional open approaches (eg, bicoronal craniotomy, transfacial, facial de-gloving, etc) or minimally invasive approaches (endoscopic endonasal approach [EEA]). As endoscopic instrumentation has advanced and the experience of skull base surgeons has transcended continents, the standard approach for most tumors is becoming the EEA [23,24]. While open approaches strive to achieve an en-bloc resection, the EEA uses a more piecemeal approach. Given that wide surgical margins is often not possible, the oncologic and survival outcomes of both approaches are comparable [23,24]. In tumors, which require the resection of the orbit or a portion of the face, an open approach is often selected. However, in nearly all other cases, the EEA is an excellent option with far less morbidity compared with a craniotomy [25].
Typically, EEAs require a piecemeal resection of the tumor with liberal use of frozen-section pathology. Although initially criticized as oncologically unsound, a growing body of literature suggests that endoscopic surgery does not compromise oncologic control or survival, and there is significantly less operative morbidity compared with traditional craniofacial resection [25-32]. However, most patients with advanced disease undergo craniofacial resection for tumor that is not amenable to gross total excision by an endoscopic approach [30,31].
Radiation therapy
Indications — RT is an important component of local-regional management for patients with nasal cavity tumors. Potential indications include:
●RT alone as local therapy for patients with unresectable or medically inoperable disease.
●RT as an adjuvant following surgery is indicated for all patients except for those with completely resected T1N0 tumors without high-grade histology, perineural invasion [10], or close or positive margins.
●Adjuvant RT is also indicated for most cases undergoing endoscopic resection because of the risk of residual disease after a piecemeal resection.
●RT may have a role as palliative treatment to treat local symptoms for patients with metastatic disease at presentation.
Dose/fractionation — The dose and fractionation regimen of RT for nasal cavity tumors is similar to that in other head and neck cancers. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)
●Primary RT for gross disease is delivered to the maximum tolerated dose of 66 to 70 Gy at 2 Gy per fraction once daily. Twice daily (accelerated hyperfractionation) schedule to a dose of 74.4 Gy in 1.2 Gy fractions is also an option. Although not widely used, accelerated hyperfractionation has theoretical advantages when the high-risk target volume is in close proximity or overlapping the visual pathways. A lower dose per fraction may reduce the risk of toxicity to the visual pathway [33-36], and accelerated therapy can potentially improve disease control. Irrespective of the fractionation regimen, the ability to deliver RT doses >60 Gy are often precluded by proximity of gross disease to the brain and/or optic structures and the associated risk of treatment-induced neurologic injury.
●In patients treated postoperatively, the typical dose for low-risk microscopic residual disease is 60 Gy at 2 Gy per fraction, whereas high-risk postoperative patients (who have received a gross total resection with positive margins) are treated to between 66 and 70 Gy at 2 Gy per fraction [37-40].
Technique — Intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), and heavy particle techniques have largely replaced older three-dimensional (3D)-conformal techniques for nasal cavity tumors. These approaches provide more conformal dose delivery and are more effective at minimizing radiation to normal tissues and, thus, minimize toxicity [40-43]. (See "General principles of radiation therapy for head and neck cancer", section on 'External beam radiation therapy' and "Radiation therapy techniques in cancer treatment".)
●IMRT – In one series of 37 patients with sinonasal tumors treated with postoperative IMRT, locoregional two-year progression-free survival was 75 percent [41]. Patients treated with IMRT did not experience grade ≥3 visual toxicity [41], whereas older two-dimensional (2D) and 3D-conformal RT techniques led to significantly higher rates of vision loss.
Other modern IMRT series still demonstrate the ongoing challenge in achieving adequate local control. In another series of 122 patients with primary and recurrent sinonasal cancers (99 treated with postoperative RT), three- and five-year local control rates were only 60 and 51 percent, respectively [43].
●Charged particle therapy – There is increasing interest in charged particle therapy (primarily protons) for the management of sinonasal tumors [44-49], primarily because the unique properties of the Bragg Peak allow for a more favorable dose distribution compared with IMRT. (See "Radiation therapy techniques in cancer treatment", section on 'Particle therapy'.)
Although there are no prospective comparative trials, a systematic review demonstrated improved outcomes using charged particles compared with photon irradiation for sinonasal cancers [45]. This analysis included data from 41 observational studies with 1472 patients (286 treated with particle therapy and 1186 treated with photon therapy). The patient characteristics were similar between the two groups except that high-grade histologies were more common in patients treated with photon therapy compared with those managed with particle therapy (50 versus 27 percent). Charged particle therapy was significantly more effective in terms of overall survival, local-regional control, and disease-free survival. There was a nonsignificant trend toward less ocular toxicity with particle therapy compared with IMRT, but there was a significant increase in overall neurologic toxicity. An enhanced radiobiological effect at the end of the proton Bragg peak can potentially increase the risk of CNS toxicity. Improvement in long-term survivorship care and aggressive imaging follow-up may also contribute to increased observation of late CNS toxicity. Our understanding of the potential benefits and shortcoming of charge particle therapy in this disease site continue to evolve. At this point, the finding of increased long-term neurotoxicity remains concerning, but requires further validation. (See "Radiation therapy techniques in cancer treatment", section on 'Radiation side effects' and "Management of radiation injury", section on 'Central nervous system syndrome'.)
Additional single- and multi-institution series further support the role of proton therapy for sinonasal cancers [50-52].
•In a series of 84 patients (high-grade histologies in 51 percent, locally advanced T3/4 disease 94 percent), most patients underwent surgical resection prior to proton therapy [50]. Nearly all received a dose-intensified, accelerated, hyperfractionated regimen (median dose, 73.8 Gy relative biological effectiveness [RBE]) with concurrent chemotherapy. Local control, neck control, freedom from distant metastasis, disease-free survival, cause-specific survival, and overall survival rates were 83, 94, 73, 63, 70, and 68 percent, respectively, at three years. Proton therapy after gross total resection resulted in a 90 percent three-year local control rate. In another series of 54 patients treated with proton therapy for sinonasal squamous cell carcinoma, the five-year local control rate was 80 percent [51].
•Another multi-institutional retrospective analysis of 69 patients treated with proton therapy for primary or recurrent sinonasal cancers concluded that proton therapy is safe and effective [52]. Among treatment-naïve patients, the three-year overall survival, freedom from distant metastasis, freedom from disease progression, and freedom from locoregional recurrence were 100, 84, 77, and 93 percent, respectively, and for those treated with re-irradiation, these rates were 76, 47, 32, and 34 percent, respectively.
Treatment planning — The general approach to treatment planning for external beam RT is discussed separately. (See "Radiation therapy techniques in cancer treatment", section on 'Treatment planning'.)
Treatment planning for tumors of the nasal cavity uses information from preoperative computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET) scans, operative reports, and postoperative treatment planning images (CT, MRI) to delineate the target volumes. In addition, communication from the surgeon is important, especially after piecemeal endoscopic resection, where margin status may have less meaning than surgeon assessment of at-risk regions. Treatment fields should encompass any residual disease (gross tumor volume), the intermediate-risk target volume (entire operative bed and areas at risk for microscopic spread of disease at the primary site), and a margin to account for uncertainties in target localization and inherent to the treatment planning process.
Management of the neck — Lymph node metastases are present at diagnosis in 10 to 20 percent of patients with squamous cell carcinoma but are less common in other histologic variants [7,53-55]. Elective neck management (either neck dissection or RT) is generally indicated for patients with T3-4 N0 M0 squamous cell carcinoma and other high-grade histologies of the nasal cavity. In the absence of clinically positive adenopathy, elective neck management can be avoided in low-grade T1-2 N0 M0 disease. However, with high-grade T1-2 N0 M0 tumors (non-adenoid cystic histology), we recommend elective lymph node irradiation.
The results of elective neck management are illustrated by a series of 71 patients with olfactory neuroblastoma [56]. With a median follow-up of 80 months, the rate of neck relapses among clinically negative (N0) patients was 18 percent. Elective neck irradiation was associated with significantly improved regional nodal control at five years compared with observation (100 percent versus 82 percent); however, there was no improvement in overall survival or disease-free survival. Of the 11 isolated neck recurrences, six were successfully salvaged with neck surgery and further RT. (See "Management of the neck following definitive radiotherapy with or without chemoradiotherapy in head and neck squamous cell carcinoma".)
Despite the potential advantages in disease control and the relatively low morbidity, there remains significant controversy regarding management of the neck for other locally advanced disease with nonsquamous cell histologies, especially olfactory neuroblastoma [57]. (See "Olfactory neuroblastoma (esthesioneuroblastoma)", section on 'Management of the neck'.)
Elective management of the neck should be considered whenever the risk of nodal metastatic disease exceeds 15 percent. Bilateral cervical lymph node stations and levels IB, II though IV, and supraclavicular lymph nodes should be addressed (figure 2).
Concurrent chemoradiation — Concurrent definitive CRT may be offered to patients with unresectable disease or high-grade histologies. Indications for adjuvant CRT include gross residual tumor after surgery, positive margins, and extracapsular nodal extension, based upon extrapolation from data from other head and neck mucosal disease sites [7,38]. The use of concurrent CRT should be limited to patients with an excellent performance status. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)
Is there a role for adjuvant chemotherapy? — The role of adjuvant systemic chemotherapy for nonmetastatic nasal cavity cancers is not established, as there are no well-conducted trials evaluating this approach.
SINONASAL UNDIFFERENTIATED AND SMALL CELL CARCINOMA — For patients with locoregionally advanced, nonmetastatic sinonasal undifferentiated carcinoma (SNUC) and small cell carcinoma, the optimal sequencing of these therapies is not known. The ideal treatment approach is typically multimodal and maximizes treatment response and minimizes patient morbidity. (See "Paranasal sinus cancer", section on 'Sinonasal undifferentiated carcinoma'.)
Surgery versus definitive chemoradiation — For patients with surgically resectable disease, some experts offer surgical resection using an endoscopic endonasal approach (EEA) to achieve a gross total resection, followed by postoperative radiation or chemoradiation (CRT). For patients who require an open resection or when EEA will not achieve negative surgical margins, definitive CRT is offered.
The survival outcomes in SNUC are comparable between surgery with postoperative radiation therapy and definitive CRT [58]. If an open approach is needed to achieve a gross total resection, definitive CRT may provide similar survival with less morbidity. However, if an EEA can achieve a gross total resection and a lowered dose of RT is given postoperatively (60 Gy instead of 70 to 74 Gy), the morbidity will likely be less than definitive CRT. This treatment approach is preferred by some of our experts, when possible.
Induction chemotherapy — For select patients with SNUC or small cell carcinoma with initially unresectable disease, other experts offer induction chemotherapy followed by response-assessment-based selection of definitive therapy [59].
For patients with sinonasal small cell carcinoma, we offer two to three cycles of induction cisplatinum and etoposide for small cell carcinoma, extrapolating from treatment of small cell carcinoma of the lung. For those with SNUC, we offer either cisplatin and etoposide or the three-drug combination of docetaxel, cisplatinum, and fluorouracil (table 2 and table 3).
●For patients who respond to induction chemotherapy, we offer definitive CRT rather than surgery.
●For those with limited responses to induction chemotherapy and resectable disease, we first offer surgical resection with or without adjuvant RT rather than CRT. Patients who are not eligible for further surgery may be offered either definitive CRT or palliative systemic therapies, similar to the approach used for patients with metastatic or recurrent head and neck cancer. (See "Treatment of metastatic and recurrent head and neck cancer".)
Induction chemotherapy is increasingly being used for cytoreduction prior to curative surgery and radiation to debulk locally advanced or borderline-resectable chemosensitive neuroendocrine variant tumors, such as sinonasal undifferentiated carcinoma and small cell carcinoma [60,61]. However, there are no prospective trials, and one observational meta-analysis suggested that chemotherapy did not improve survival in over 700 patients with sinonasal neuroendocrine carcinomas [62,63]. Additionally, using response to induction chemotherapy to select for or against surgery may potentially be a risky strategy for patients with SNUCs that do not respond to chemotherapy, as it runs the risk of converting resectable disease into unresectable disease. Nevertheless, clinical response to induction chemotherapy may be a critical predictive and prognostic factor in the subsequently selecting for the optimal primary treatment approach (eg, surgery or definitive CRT [59]).
As an example, one observational study evaluated outcomes in 95 patients with treatment-naïve sinonasal undifferentiated carcinoma who were treated with induction chemotherapy (a majority using cisplatin and etoposide) followed by either surgery or definitive CRT [59]. Among patients with partial or complete response to induction chemotherapy, definitive CRT was associated with improved disease-specific survival (DSS) relative to definitive surgery followed by adjuvant RT or CRT (five-year DSS 81 versus 54 percent). By contrast, among patients without at least a partial response to induction chemotherapy, surgery followed by adjuvant RT or CRT was associated with an improved DSS relative to CRT (five-year DSS 39 versus 0 percent).
TREATMENT OF METASTATIC DISEASE — In patients with locally advanced or metastatic tumors when surgery and radiation therapy are contraindicated or can no longer control the disease effectively, we offer palliative treatment with systemic chemotherapy [7]. When such chemotherapy is indicated, our approach generally is to use a platinum-based combination. The general approach to the treatment of such patients is similar to that of other head and neck cancers and is discussed in detail separately. (See "Treatment of metastatic and recurrent head and neck cancer".)
PROGNOSIS — Local-regional disease control is the major driver of morbidity and mortality for tumors of the nasal cavity. The outcomes from some of the largest contemporary series are shown in the table (table 4).
●Local-control rates range from approximately 60 to 80 percent at five years and generally mimic overall survival rates [64].
●Leptomeningeal dissemination is a common form of distant metastasis, especially in patients with intracranial invasion and high-grade neuroendocrine histology. In a series of 120 patients, leptomeningeal dissemination accounted for 45 percent of isolated metastases [65].
●Distant visceral metastatic spread is uncommon in patients who achieve continuous local-regional control of disease and occurs in 15 to 20 of such patients. Distant metastases may be more common in patients with adenoid cystic carcinoma [47,66-68], undifferentiated histology [69], or node positive disease [54].
Important prognostic factors for disease control include T stage, histology, orbital invasion, cribriform plate invasion, dural invasion, cavernous sinus invasion, and extent of surgical resection. Human papillomavirus (HPV) status for nasal cavity squamous cell cancers may also be important.
TOXICITY — Severe toxicity is frequent after curative-intent therapy with surgery and radiation therapy (RT), given the proximity to a range of critical structures. (See "Management of late complications of head and neck cancer and its treatment" and "Delayed complications of cranial irradiation".)
●Eye and visual pathways – Damage to the lacrimal apparatus, conjunctiva, and cornea is common and can result in epiphora (excessive tearing), painful dry eyes, or corneal ulceration. Injury to the lens can lead to cataracts. Damage to the retina, macula, optic nerves, and/or chiasm can result in vision loss.
Serious (grade 3 or 4) acute and late visual toxicity has been reported in up to 56 and 24 percent of patients, respectively, after RT for sinonasal tumors [22,41,70]. However, the rate of serious visual pathway toxicity has improved with the use of contemporary RT techniques [41,42,71-75]. (See 'Technique' above.)
●Central nervous system – RT toxicity may be manifested by cognitive dysfunction, brain/brainstem necrosis, or stroke. Damage to the hypothalamus/pituitary axis may result in neuroendocrine disorders.
●Soft tissue and bone necrosis – Nasal irritation and chronic rhinosinusitis are common. Bone necrosis has also been reported.
●Radiation-induced chronic rhinosinusitis – RT-induced toxicity to sinonasal mucosa leads to impaired nasociliary clearance as well as impaired mucous production or xerorhinia. The result is the production of thick secretions with decreased nasal clearance. Patients are often left with thick, foul-smelling crusts obstructing their nasal passages. Frequent in-office debridement, nasal irrigation, and a nasal steroid may be necessary to manage this chronic condition [76].
POSTTREATMENT SURVEILLANCE — Follow-up approximately every three months is warranted during the first two years after curative-intent therapy since 80 to 90 percent of all recurrences occur during this period. However, routine scheduled follow-up evaluation for cancer surveillance should continue for five years. Recurrences beyond five years are most commonly encountered in histologies such as adenoid cystic carcinoma and olfactory neuroblastoma.
Follow-up should include a history and physical examination, including endoscopic evaluation of the mucosa of the upper aerodigestive tract to survey for both local disease recurrence and second primary head and neck malignancies. Magnetic resonance imaging (MRI) is indicated for evaluation of local, skull base, perineural, and leptomeningeal recurrence as well as for evidence of radiation necrosis. Surveillance with computed tomography (CT) or positron emission tomography (PET)-CT may be indicated for node-positive disease or in advanced cases of adenoid cystic carcinoma, undifferentiated carcinoma, or mucosal melanoma. A CT or MRI obtained three to four months after treatment can serve as a baseline for future reference since, in postoperative patients, the anatomy is altered. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)
Survivors should also undergo periodic ophthalmologic, audiometry, and neuroendocrine functional assessments. Neurocognitive evaluation is performed on a case-by-case basis.
In good performance status patients, local recurrences that are amenable to complete resection have generally been managed surgically, although the prognosis remains poor. Neck recurrences outside the prior radiation therapy field can also be managed with surgery and postoperative radiation therapy. (See "Treatment of locally recurrent squamous cell carcinoma of the head and neck".)
A contemporary study at a high-volume skull base center of excellence developed an algorithm to stratify patients with recurrent sinonasal carcinomas. Patients with low-grade lesions, no orbital invasion, and no skull base invasion were found to have good prognosis with aggressive treatment, and salvage surgery was recommended. Patients with high-grade tumors, orbital invasion, or skull base invasion were further divided into those with tumors in the ethmoids and all other locations. Patients in the ethmoid group had fair prognoses, and surgery could be considered with caution. Those in the latter group had dismal outcomes and were recommended for palliative care only [77].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)
SUMMARY AND RECOMMENDATIONS
●Tumors arising in the nasal cavity have a natural history similar to that of tumors of the paranasal sinuses. Initial diagnostic and staging evaluation should include a complete history and physical examination, endoscopic evaluation of the primary site, computed tomography (CT)/magnetic resonance imaging (MRI), and baseline functional assessments of the tissues at risk of tumor involvement and therapeutic interventions. (See 'Initial evaluation' above and 'Staging' above.)
●For patients with resectable early-stage and locoregionally advanced disease (excluding sinonasal undifferentiated carcinoma and small cell carcinoma histologies), we suggest surgical resection and adjuvant radiation therapy (RT) rather than either surgery or RT alone (Grade 2C). (See 'Treatment of locoregional disease' above and 'Approach' above.)
•We suggest postoperative RT rather than preoperative RT to minimize the risk of wound-healing complications (Grade 2C). (See 'Radiation therapy' above.)
●For patients with unresectable disease (excluding sinonasal undifferentiated carcinoma and small cell carcinoma histologies), we offer combined modality therapy with cisplatin-based chemotherapy and RT. Supporting data are discussed elsewhere. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)
•For those who require significant tumor reduction to allow more favorable radiation treatment volumes with less morbidity to proximal structures such as the eye, brain, or swallowing apparatus, we suggest incorporation of induction chemotherapy prior to concurrent chemoradiation (CRT) (Grade 2C). (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Induction chemotherapy'.)
●For patients with locoregionally advanced, nonmetastatic sinonasal undifferentiated carcinoma and small cell carcinoma histologies, the ideal treatment approach is typically multimodal and maximizes treatment response and minimizes patient morbidity.
•For patients with resectable disease, some experts offer surgical resection followed by postoperative radiation or CRT. For those who require an open resection or when surgery is not predicted to achieve negative margins, definitive CRT is offered. (See 'Surgery versus definitive chemoradiation' above.)
•For select patients with initially unresectable disease, other experts offer induction chemotherapy followed by a response-assessment-based selection of definitive therapy. (See 'Induction chemotherapy' above.)
-For those who respond to induction chemotherapy, we suggest definitive CRT rather than surgery (Grade 2C).
-For those with limited responses to induction chemotherapy and resectable disease, we suggest surgery if feasible (with or without adjuvant RT) rather than CRT (Grade 2C). For patients who are not surgical candidates, options include CRT or palliative systemic therapies.
●We suggest prophylactic nodal irradiation of bilateral cervical lymph node stations and levels IB, II through IV (figure 2) for patients with stage T3 to T4 disease, tumor extension to areas rich in lymphatics (ie, nasopharynx), as well as all patients with an olfactory neuroblastoma or sinonasal undifferentiated carcinoma (Grade 2C). (See 'Management of the neck' above.)
●For patients receiving RT, particle therapy (ie, proton therapy) is an alternative to standard intensity-modulated radiation therapy (IMRT). The rationale is to deliver dose-escalated therapy and reduce the risk of serious treatment-related toxicity. (See 'Radiation therapy' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges John Werning, MD, DMD, FACS, and Anamaria Yeung, MD, who contributed to an earlier version of this topic review.
