Sinonasal carcinomas are uncommon neoplasms accounting for approximately 3% to 5% of all upper respiratory tract malignancies. Sinonasal malignancies in most cases do not cause early symptoms and present in an advanced stage of disease. Exact staging necessitates a clinical and endoscopic examination with biopsy and imaging. Tumor resection using an open or endoscopic approach is usually considered the first treatment option. In general, sinonasal carcinomas are radiosensitive, so adjuvant or neoadjuvant radiation treatment may be indicated in advanced disease. Multidisciplinary surgical and medical oncologic approaches, including ablation and reconstruction, have enhanced the survival outcome over the past few decades.
Key points
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Sinonasal malignancies are uncommon neoplasms, and in most cases present in an advanced stage of disease.
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Exact staging necessitates a clinical and endoscopic examination with biopsy and imaging.
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Tumor resection using an open or endoscopic approach is usually considered as the first treatment option.
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In general, sinonasal carcinomas are radiosensitive and, therefore, adjuvant or neoadjuvant radiation treatment may be indicated in advanced disease.
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Multidisciplinary surgical and medical oncologic approaches, which include ablation and reconstruction, have enhanced the survival outcome over the past few decades.
Introduction
Sinonasal carcinomas are uncommon neoplasms that account for approximately 3% to 5% of all upper respiratory tract malignancies. Sinonasal malignancies in most cases do not cause early symptoms and present in an advanced stage of disease. In general, sinonasal carcinomas are radiosensitive; therefore, adjuvant or neoadjuvant radiation treatment may be indicated in advanced disease. Multidisciplinary surgical and medical oncologic approaches, which include ablation and reconstruction, have enhanced the survival outcome over the past few decades.
Epidemiology
Sinonasal carcinomas are uncommon malignancies, with an estimated incidence in the United States of 0.556 cases per 100,000 population. This figure represents approximately 0.2% of all cancers and 3% to 5% of cancers in the upper aerodigestive tract. The majority of published reports have identified the maxillary sinus to be the most common primary site. Other studies have reported this to be the nasal cavity. Because sinonasal malignancies often present in an advanced stage, the true identification of the site of origin may be difficult. Primary malignancy of the frontal sinus is uncommon, and those arising in the sphenoid sinus are rare.
Sinonasal carcinomas arise most often during the sixth decade of life with a male to female ratio of approximately 2:1. A recent study of population-based data (Surveillance, Epidemiology, and End Results [SEER]) included more than 6000 patients, and reported a decrease in the incidence of sinonasal cancer in men while remaining stable among women. These findings reflect changing demographics and the socioeconomic developments seen also in other head and neck cancers.
Risk Factors
Several occupational risk factors have been reported. Adenocarcinomas have been associated with hardwood dust exposure, chrome pigment, clothing, and leather, whereas squamous cell carcinoma (SCC) has been linked with nickel, soft wood dust, radium, mustard gas, and asbestos. Occupational exposures such as those involving the use of formaldehyde have been shown to increase the risk of both adenocarcinoma and SCC. Unlike other head and neck cancers, cigarette smoking and alcohol have less impact on the development of sinonasal carcinoma.
More recently, human papilloma virus (HPV) has also been associated with the malignant transformation of inverted papilloma and SCC. Similar to HPV-associated SCC of the oropharynx, tumors in the sinonasal region that are HPV positive have a better treatment outcome.
Introduction
Sinonasal carcinomas are uncommon neoplasms that account for approximately 3% to 5% of all upper respiratory tract malignancies. Sinonasal malignancies in most cases do not cause early symptoms and present in an advanced stage of disease. In general, sinonasal carcinomas are radiosensitive; therefore, adjuvant or neoadjuvant radiation treatment may be indicated in advanced disease. Multidisciplinary surgical and medical oncologic approaches, which include ablation and reconstruction, have enhanced the survival outcome over the past few decades.
Epidemiology
Sinonasal carcinomas are uncommon malignancies, with an estimated incidence in the United States of 0.556 cases per 100,000 population. This figure represents approximately 0.2% of all cancers and 3% to 5% of cancers in the upper aerodigestive tract. The majority of published reports have identified the maxillary sinus to be the most common primary site. Other studies have reported this to be the nasal cavity. Because sinonasal malignancies often present in an advanced stage, the true identification of the site of origin may be difficult. Primary malignancy of the frontal sinus is uncommon, and those arising in the sphenoid sinus are rare.
Sinonasal carcinomas arise most often during the sixth decade of life with a male to female ratio of approximately 2:1. A recent study of population-based data (Surveillance, Epidemiology, and End Results [SEER]) included more than 6000 patients, and reported a decrease in the incidence of sinonasal cancer in men while remaining stable among women. These findings reflect changing demographics and the socioeconomic developments seen also in other head and neck cancers.
Risk Factors
Several occupational risk factors have been reported. Adenocarcinomas have been associated with hardwood dust exposure, chrome pigment, clothing, and leather, whereas squamous cell carcinoma (SCC) has been linked with nickel, soft wood dust, radium, mustard gas, and asbestos. Occupational exposures such as those involving the use of formaldehyde have been shown to increase the risk of both adenocarcinoma and SCC. Unlike other head and neck cancers, cigarette smoking and alcohol have less impact on the development of sinonasal carcinoma.
More recently, human papilloma virus (HPV) has also been associated with the malignant transformation of inverted papilloma and SCC. Similar to HPV-associated SCC of the oropharynx, tumors in the sinonasal region that are HPV positive have a better treatment outcome.
Pathology
Anatomy
The nasal cavity and the paranasal sinuses are in close proximity to many vital structures that can be involved by the contiguous spread of tumor. In addition, the paranasal sinuses have lymphatic and venous drainage pathways, which provide additional routes of spread intracranially. The skull base forms the floor of the cranial cavity and separates the brain from a variety of other important facial structures. The bony architecture of the skull base consists of the ethmoid, sphenoid, occipital, paired frontal, and parietal bones. Three regions can be differentiated: the anterior, middle, and posterior cranial fossae. In the case of sinonasal malignancy, the anterior skull base is the most commonly affected region. Thus, exact anatomic knowledge of the paranasal sinuses and anterior skull base is important for the treatment of sinonasal malignancies.
Staging
Because of late presentation, the diagnosis of malignant sinonasal tumors in patients often occurs in the later stages, so it is difficult to determine the exact site of tumor origin. The first staging system was described by Ohngren, and was based on resectability criteria established by the extension of the tumor with respect to Ohngren’s line (connecting the angle of the mandible with the medial canthus). Since then, a variety of classification systems have been published, including the seventh TNM classification system by the American Joint Committee on Cancer (AJCC). There is a recognized correlation between tumor extension and treatment outcome. A review by the International Collaborative Group demonstrated that the histology, grade, intracranial extent, and status of surgical margins were independent predictors of treatment outcome. The different staging systems for olfactory neuroblastoma are separately described in the relevant section of this article.
Histologic subtypes
Sinonasal carcinomas present with a variation of histologic heterogeneity in tumor type. The sinonasal tract and skull base is a region with the greatest histologic diversity in the body, and this is reflected in the extensive disorder classification list compiled by the World Health Organization (WHO). The major malignant subtypes are presented in Box 1 . This article reviews the more common epithelial, neuroectodermal, and neuroendocrine type tumors. There are other more rare malignancies (eg, bone or soft-tissue tumors) that may also occur.
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Epithelial
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Squamous cell carcinoma
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Adenocarcinoma
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Salivary-gland type tumors
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Adenoid cystic carcinoma
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Mucoepidermoid carcinoma
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Acinic cell carcinoma
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Sinonasal undifferentiated carcinoma
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Neuroectodermal
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Melanoma
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Olfactory neuroblastoma
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Neuroendocrine
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Sinonasal neuroendocrine carcinoma
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Soft-tissue tumors
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Borderline and low malignant potential tumors of soft tissue
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Malignant tumors of bone and cartilage
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Hematolymphoid tumors
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Neuroectodermal tumors
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Germ cell tumors
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Secondary tumors
Squamous Cell Carcinoma
The most commonly encountered malignant neoplasms of the sinonasal tract are the keratinizing and nonkeratinizing types of SCC. In 1% to 7% of all cases, SCC is seen in association with inverted papilloma. SCC of the nasal cavity arises in the paranasal sinuses more frequently than in the nasal cavity. The majority of SCC of the paranasal sinuses are keratinizing and nonkeratinizing lesions, with the undifferentiated type being less frequent. The latter subtype shows a more rapid course of growth. Similar to other locations in the head and neck, the basaloid variant of SCC has a more aggressive biological behavior.
Early-stage disease (T1/T2) arising from the nasal cavity can be effectively managed by single-modality treatment (surgery or radiotherapy), whereas advanced-stage disease (T3/T4) requires a combined approach. SCC of the paranasal sinuses is often diagnosed at a late stage, and regional spread to the lymph nodes may be present. Therefore elective treatment of the neck may be considered, especially when the SCC of the paranasal sinuses has invaded the overlaying soft tissue or adjacent bony structures. The 5-year survival rates reported for SCC of the paranasal sinuses and the nasal cavity range from 40% to 70%.
Adenocarcinoma
Adenocarcinoma represents the third most common malignancy in the sinonasal tract, after SCC and adenoid cystic carcinoma. It accounts for approximately 15% of all sinonasal cancers and is associated with certain risk factors. Adenocarcinoma is male dominant and presents most frequently in the ethmoid sinuses. This malignancy is divided into a salivary-gland and non–salivary-gland type. The latter is further separated into intestinal and nonintestinal types. Subclassifications of the intestinal type include papillary, colonic, solid, mucinous, or mixed, and the nonintestinal types are classified as either low or high grade. Intestinal-type carcinomas are generally aggressive with a local recurrence rate of up to 50%, lymphatic spread in 10%, and a distant metastasis rate of 20%. Low-grade nonintestinal adenocarcinomas most frequently occur in the ethmoid cells, and the 5-year survival rate is up to 85%. The high-grade nonintestinal adenocarcinomas are more commonly found in the maxillary sinus and have a very poor prognosis (3-year survival approximately 20%). The majority of the adenocarcinomas arise from the mucoserous glands while the remainder originates in the respiratory epithelium.
Many patients with adenocarcinomas are effectively treated with radiotherapy. However, surgical excision followed by radiotherapy is favored in many centers throughout the world. An open radical craniofacial resection is often warranted, and in many cases adjuvant radiotherapy needs to be scheduled because the disease is usually recognized in an advanced stage. In carefully selected patients, a curative endoscopic approach may be considered. Another method of treatment involves surgical debulking via an endoscopic or open approach in combination with repeated topical chemotherapy (5-fluorouracil). Radiotherapy in this case is only given in cases of local recurrence. Ten-year survival rates are reported to exceed 70%.
Adenoid Cystic Carcinoma
Adenoid cystic carcinoma (ACC) is the second most common tumor of the nasal cavity and paranasal sinuses, and accounts for approximately 10% of all non-SCC in the head and neck region and 15% of all salivary-gland cancers. It arises more frequently in minor salivary glands than in all major salivary glands combined. Histologically, ACC exhibits 3 different subtypes based on the tumor architecture: cribriform, tubular, and solid. The cribriform pattern with its familiar stromal architecture is the most common. The tubular pattern, with a more typical glandular formation, has the best prognosis, and the less common solid pattern has the worst outcome. ACC in general is a slow-growing neoplasm, and recurrences often develop 10 to 20 years after initial treatment. ACC has a propensity for perineural spread and intracranial extension, reflecting the challenges of treating ACC and high morbidity. The most frequently involved nerves are the maxillary, mandibular, and vidian nerves. Because negative surgical resection margins may be difficult to achieve, ACC of the sinonasal tract has a poor prognosis. Lymphatic spread to regional lymph nodes is uncommon and accounts for 10% to 30% of patients, whereas distant hematogenous spread is more frequent, with an average incidence of 40%. The propensity for distant spread correlates with the stage at presentation, and the most commonly affected distant sites are the lungs and long bones.
Surgical treatment with negative surgical margins is the gold standard for treating ACC. Postoperative radiation is used to achieve better local control, although the association with increasing survival remains controversial. The role of systemic therapy is yet to be defined, although it has been shown to benefit some patients with recurrent, metastatic, and/or unresectable disease. Systemic therapy mainly consists of cisplatin alone or in combination with other agents (eg, doxorubicin, 5-fluorouracil), and the reported response rates to chemotherapy have been inconsistent and remain less than 20%.
Mucoepidermoid Carcinoma
Mucoepidermoid carcinoma (MEC) of the sinonasal tract is the second most common sinonasal salivary-gland type of malignancy after ACC. Differential diagnoses include adenosquamous carcinoma, adenocarcinoma, and necrotizing sialometaplasia. Overall, MEC accounts for fewer than 0.1% of all malignant sinonasal tract neoplasms, with no gender difference in disease prevalence. MEC are histologically graded as low, intermediate, or high grade, with the latter having the worst prognosis. Clinical symptoms are nonspecific and usually present over a period of months. Invasive growth in MEC is common and recurrence is seen in approximately one-third of patients, usually within 2 years. Surgery with the achievement of clear margins is the treatment of choice. Adjuvant radiotherapy in cases of positive margins is suggested to improve survival to the same level as that in patients with negative surgical margins. In cases of a high-grade tumor with negative resection margins, adjuvant radiotherapy is usually considered because of the aggressiveness of these tumors. Loh and colleagues reported that disease-free survival for MEC in the nasal cavity was poorer than that for MEC in the oral cavity. MEC was associated with a greater tendency for local recurrences, which may be due to the incomplete tumor resection resulting from anatomic limitations.
Acinic Cell Carcinoma
Acinic cell carcinoma is a low-grade malignant epithelial salivary-gland malignancy presenting very rarely in the sinonasal tract. Acinic cell carcinomas are most commonly found in the fifth and sixth decades of life, but are also reported in children. There is no gender preference in the occurrence of these sinonasal tumors. Acinic cell carcinoma is believed to arise from the intercalated duct reserve cells. Different grading systems and prognosis-related factors are described, but these studies are limited by small sample sizes and mainly concern major salivary glands outside the sinonasal tract. Laskawi and colleagues found that histologically well-differentiated tumors in the parotid gland correlate with better prognosis than do poorly differentiated acinic cell carcinomas. There is a very low chance of nodal spread when the tumor originates in the sinonasal tract. The treatment of choice is surgical excision with adjuvant radiotherapy in patients with positive resection margins, perineural invasion, and/or lymphovascular invasion. Similarly to ACC, patients with acinic cell carcinoma should be followed for long periods of time because metastases may occur many years after treatment.
Sinonasal Undifferentiated Carcinoma
Sinonasal undifferentiated carcinoma (SNUC) was first described by Frierson and colleagues in 1986. SNUC is a very rare and aggressive malignancy that is hypothesized to be part of the spectrum of neuroendocrine carcinomas that include olfactory neuroblastoma, neuroendocrine carcinoma, and small cell carcinoma. Usually it incorporates extensive tissue destruction and involvement of the orbit and anterior cranial fossa. In general, light microscopy can differentiate between SNUC and other differential diagnoses such as olfactory neuroblastoma, lymphoma, rhabdomyosarcoma, and melanoma. In some cases, immunohistochemistry or electron microscopy is required to confirm the diagnosis. Differentiation between SNUC and olfactory neuroblastoma is important because the clinical behavior, prognosis, and treatment differ: olfactory neuroblastoma is generally slow growing with a better prognosis, whereas SNUC progresses more rapidly with a poor prognosis. SNUC has been associated with Epstein-Barr virus; however, its role has not yet been confirmed. The best treatment strategy for these tumors has yet to be defined. Some physicians have described preoperative chemotherapy followed by radiotherapy. In cases with no extensive intracranial involvement and without the presence of distant disease, a definitive surgical resection can be performed. A recent meta-analysis of treatment outcomes for SNUC reported that treatment should include surgery, with radiation and/or chemotherapy as adjunctive treatments. The role of induction chemotherapy in limiting the extent of surgery remains to be established.
Melanoma
Melanoma of the sinonasal tract is rare and accounts for only 1% of all melanomas. The nasal cavity is the most commonly affected site, followed by the maxillary antrum and the ethmoid sinuses, and it usually occurs between the fifth and eighth decades of life. Clinical examination can be challenging when the melanoma is amelanotic because the typical heavily pigmented polypoid or fleshy mass is absent. Several histologic subtypes are described: amelanotic small blue cell, pleomorphic, epithelioid, spindle cell, and myxoid. All of these subtypes show a high mitotic rate, vascular invasion, regression, and absence of tumor-infiltrating lymphocytes. Usually the presence of melanin helps to confirm the diagnosis. However, in the absence of melanin, specific stains are used to differentiate mucosal melanoma from other diagnoses such as anaplastic carcinoma, lymphoma, and olfactory neuroblastoma. In general, the prognosis of patients diagnosed with sinonasal mucosal melanoma is poor, with an average 5-year actuarial survival rate of less than 15%. Patients with lesions that present on the nasal septum tend to do better than those with lesions at other sites within the sinonasal tract. Primary treatment is surgery, either endoscopically or via an open resection. Radiotherapy may help to improve locoregional control; however, it does not affect overall survival. There is limited evidence suggesting that prolonged survival is realized with the addition of chemotherapy, such as dacarbazine, platinum analogues, nitrosoureas, microtubular toxins, or taxols. Further prospective, randomized clinical trials are necessary to confirm any definitive outcome effect.
Olfactory Neuroblastoma
Olfactory neuroblastoma is an uncommon malignancy hypothesized to arise from the olfactory epithelium. Its uncertain origin has resulted in different names; however, the most common terms used in the literature are olfactory neuroblastoma and esthesioneuroblastoma. This neoplasm accounts for approximately 7% to 10% of all sinonasal malignancies, and occurs with a bimodal peak in the second and sixth decades of life. Impairment or a loss of the sense of smell, as one might expect, is not a common presentation because the contralateral part of the olfactory system is often still preserved. The initial stage of the disease is highly correlated with survival outcome. Several clinical staging systems have evolved over the past decades: the Kadish staging system, described in 1976, is the first and most commonly used staging system incorporating 3 groups: group A contains tumors confined to the nasal cavity, group B tumors involving the paranasal sinuses, and group C tumors that extend beyond the sinonasal cavity. This system was modified by Foote and colleagues with the addition of stage D, which includes cervical or distant metastasis. A third system, based on the TNM classification system, has been described by Dulguerov and Calcaterra ( Box 2 ). In addition, a histologic grading system reported by Hyams describes 4 different grades, from Grade I (well differentiated) to Grade IV (undifferentiated). The grading is based on growth, architecture, mitotic activity, necrosis, nuclear polymorphism, rosette formation, and fibrillary stroma. There is a lack of consensus of whether this grading system is predictive of outcome. The most frequently used approach for treating olfactory neuroblastoma is a combined approach with radiotherapy given either before or after surgical resection. Patients diagnosed with Kadish stage A or stage T1 lesions may not require adjuvant radiotherapy if clear surgical margins are achieved. To obtain adequate surgical margins, the cribriform plate is resected en bloc. The classic combined anterior craniofacial resections have been replaced by expanded endoscopic approaches in selected cases, without impact on the 5-year control rate. The 5-year disease-specific survival is reported to range from 52% to 90%. Although olfactory neuroblastoma is not generally believed to be chemosensitive, some centers have advocated adjunctive chemotherapy to the treatment for Kadish B or C lesions. However, this combined-therapy approach has not been widely accepted.
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