Sinonasal neuroendocrine malignancies are complex and rare, with ENB representing the most undifferentiated end of the spectrum of neuroendocrine tumours. ENB accounts for approximately 3% to 6% of nasal cavity and paranasal sinus cancer cases, 0.3% of upper aerodigestive tract malignancies and less than 1% of all head and neck cancers. This tumour shows no predilection for gender and occurs over a wide age range, though a bimodal age distribution with an early peak from 11 to 20 and a later peak between 51 and 60 years of age has been reported [2, 4].
ENB is characterized by slow progression and locally aggressive behaviour, which lead to long-term survival but very frequent late local recurrence. The aggressiveness of ENBs is partly due to their complex anatomical location, close to vital structures, which is associated with non-specific symptoms that lead to delay in the patient seeking diagnosis [1, 5, 6]. The reported case revealed an atypical ENB identified by oral symptoms, with radiographic images that suggested a maxillary neoplasm invading the nasal cavity. However, axial CT images suggested that the epicentre of the lesion was in the nasal region and that it was invading the alveolar process (Figure 2).
The diagnosis of ENB via light microscopy by itself can be difficult since the tumour tends to exhibit little or no differentiation. Pathological classification is challenging because the tumours must be differentiated from other small cell neoplasms of the nasal cavity such as Non-Hodgkin’s lymphoma, Ewing’s sarcoma, mucosal malignant melanoma and neuroendocrine carcinomas . In this case, given the relation with the oral mucosa, basaloid squamous cell carcinoma was also included in the differential diagnosis.
The histopathological parameters that help in differentiating these tumours include the pattern of tumour cell arrangement, stroma, nuclear chromatin characteristics, presence or absence of neuropil and resetting. The use of a broad panel of antibodies in immunohistochemical staining may help to establish a final diagnosis. ENB is usually positive for general neuroendocrine markers, such as neuron specific enolase (NSE), S-100 protein, synaptophysin (Syn) and chromogranin. NSE is typically the most positive immunohistochemical stain in ENB. S-100 protein positive peripheral dendritic cells corresponding to Schwann cells may be present within the neoplasm or at the edges of tumour nests. Positivity varies in the cases reported in the literature for vimentin, keratin, glial fibrillary acidic protein, and neurofilaments [5, 6]. In the reported case the tumour showed strong positive expression of NSE, Syn and vimentin. Significant correlation between CD44 expression and the stage of the disease has been suggested to help predicting clinical outcome. CD44s negative tumors are significantly correlated with the lack of differentiation. Thus, overexpression of CD44s could be considered as a predictor of the absence of infiltration of the tumour and neuroblastic tumors subtypes of favorable prognosis .
The possibility of basaloid squamous cell carcinoma and primitive neuroendocrine tumour was not supported by immunohistochemistry, and this was reinforced by the focal expression of carcinoembryonic antigen and pan-cytokeratin. The small number of labeled cells at P53 suggested a more favorable prognosis in terms of tumour proliferation .
The rates of primary tumour recurrence vary and most of the case series show local recurrence rates of approximately 14 to 30%. The mean time to recurrence is 2 years, but recurrences can occur as late as 10 years after the initial diagnosis, with approximately 50% of them occurring after 5 years [1, 5, 6, 8].
Craniofacial resection with definitive or adjuvant radiotherapy has been used for local control. Chemotherapy can be used in an adjuvant/neoadjuvant attempt and also in the metastatic phase, or recurrent or advanced disease, although its effectiveness has still not been established. Such multimodality therapy has become the most common approach to ENB [4, 9–12].
The Kadish staging system is a clinically based staging system for sinonasal tumors and the ENB herein described was classified as Kadish stage C (extension of tumour beyond the nasal cavity and paranasal sinuses) [9, 10]. However, sectional images showed local disease in an uncommon location, the anterior part of the inferior nasal concha extending to another atypical area – the maxillary alveolar ridge. Due to the large number of neoplasms and cystic lesions affecting the jaws, extension of the tumour into the oral cavity was causing tooth mobility, mimicking a neoplasm of that region.
In this case report, the rare oral findings produced delayed in diagnosis leading to a compromise in planning and execution of adequate management. Only another two cases of ENB in the literature included intraoral findings, confirming the importance of the knowledge about different clinical presentations of ENB [13, 14]. We believe that the difficulty in diagnosis and inadequate management due to atypical oral cavity localization may lead to a compromise in planning and execution of further radical management and thus a poor prognosis. This highlights the importance of the dentist’s knowledge about different clinical presentations of ENB. The two local recurrences of this reported case were also observed primarily in the oral cavity. Despite surgery and radiotherapy, cervical metastasis was detected 12 months after the end of treatment. Based on the histological grading, the tumor of this patient can be categorized as high-grade malignancy and along with advanced clinical stage (Kadish C) may be associated with locoregional recurrence and clinical spread of tumor.