Esthesioneuroblastoma

Etiology

The exact etiology of esthesioneuroblastoma is still unknown, and so are the predisposing factors.

Epidemiology

Esthesioneuroblastoma accounts for 2% to 6% of nasal cavity and paranasal sinus cancer cases and 0.3% of all upper aerodigestive tract malignancies.[2] The incidence of esthesioneuroblastoma seems to have increased in the last decade. Esthesioneuroblastoma may occur at any age, although it occurs predominantly in young adults. The mean age at presentation is 40 to 70 years. There is a second peak of incidence in later adult life. Men and women are affected equally.[3]

Pathophysiology

Esthesioneuroblastoma is thought to arise from specialized sensory neuroepithelial olfactory cells. These cells are normally present in the upper part of the nasal cavity, including the upper part of the septum, superior nasal concha, the roof of the nose, and the cribriform plate of the ethmoid sinus. 

Genetic profile:

Esthesioneuroblastoma demonstrates numerous chromosomal aberrations, deletions, and gains, but with no consistent pattern.[4][5] In one study, a specific deletion on chromosome 11 and a gain on chromosome 1p correlated with metastasis and a worse prognosis.[6] Gains are more frequent than losses, and high-stage esthesioneuroblastomas show more alterations than low-stage tumors. Gains in 20q and 13q may be significant in the progression of this neoplasm - these regions may harbor genes with functional relevance in esthesioneuroblastoma. The detection of PTCH1, GL/1, and GL/2 in 70%, 70%, and 65%, respectively, of human esthesioneuroblastoma specimens, suggests that the SHH signaling pathway may be involved in the pathogenesis of this neoplasm.[7] Research has found expression of the OMP and RICBB genes in esthesioneuroblastomas.

Histopathology

Macroscopic examination:

Esthesioneuroblastomas are usually unilateral, polypoid, glistening, soft, reddish-grey masses with an intact mucosa; the cut surface appears greyish-tan to pinkish-red and hyper vascularized. The tumors range from under 1 cm in size to large masses involving the nasal cavity and intracranial region. They frequently expand into the adjacent paranasal sinuses, orbit, and cranial vault.[8]

Macroscopic examination:

Low-grade esthesioneuroblastoma form submucosal, sharply demarcated nests, lobules, or sheets of cells, often separated by richly vascular or hyalinized fibrous stroma. Pseudorosettes (Homer-Wright rosettes), with neoplastic cells palisading or cuffed around the central delicate fibrillar neural matrix, may be seen. The tumor cells are often uniform, with sparse cytoplasm and round or ovoid nuclei with punctate salt-and-pepper chromatin and nucleoli that are either small or absent. Esthesioneuroblastoma characteristically demonstrates fibrillary cytoplasm and interdigitating neuronal processes (neuropil), created by a syncytium of cells. Higher-grade tumors show tumor necrosis, pleomorphism, increased mitoses, decreased to absent neuropil, and a less overt lobular growth pattern. The tumor cells can arrange in gland-like rings or tight annular formations with a true lumen (Flexner-Wintersteiner rosettes). Rosettes alone are not diagnostic of esthesioneuroblastoma, although the Homer Wright rosettes are nearly pathognomonic in the nasal cavity when containing true neuropil. The mitotic rate is variable, but is usually low, especially in lower-grade tumors. Calcifications (concretion-like or psammomatous) may be seen, less frequently as the grade increases. Melanin pigment, ganglion cells, rhabdomyoblasts, divergent differentiation as islands of true epithelium (squamous pearls or gland formation), and clear-cell change may occasionally present in esthesioneuroblastoma.[8]

Immunohistochemical study:

The typical immunohistochemical profile includes diffuse staining for neuron-specific enolase,[9] synaptophysin, chromogranin A, CD56 (NCAM) and beta-tubulin, as well as variable S100 protein reactivity, which is typically in a sustentacular cell pattern highlighting only cells at the periphery of the nests, often limited in higher-grade tumors. Sustentacular cells may also be positive for GFAP. Calretinin staining (nuclear and cytoplasmic) has been reported in esthesioneuroblastoma but can also be seen in other sinonasal tumors.[10] As many as one-third of esthesioneuroblastomas may also stain focally for cytokeratin (CAM5.2, CK18). Negative markers include CD45RB, CD99, p63, and FLl1. Proliferation marker studies reveal a variable  Ki-67 proliferation index (2- 50%), and BCL2 expression increases with tumor grade.[11][12]

History and Physical

Clinically, esthesioneuroblastoma often has a subtle presentation mimicking benign inflammatory or infectious disease, and delay in diagnosis is not uncommon. Nasal obstruction and epistaxis are typical early manifestations; however, other more specific symptoms can occur depending on the location and extent of the tumor.[13] Anosmia can precede the diagnosis of esthesioneuroblastoma by several years.[14] Other symptoms are related to extension into paranasal sinuses (facial swelling, medial canthus mass), the orbit (orbital pain, proptosis, epiphora, visual field defects), or anterior cranial fossa (headache), and manifestations of inappropriate antidiuretic hormone secretion.

Evaluation

A thorough physical exam and flexible fiberoptic endoscopic evaluation, complemented with both contrast-enhanced CT scan and MR imaging, are key in the diagnostic workup.

Physical exam:

Any patient with a history that is suspicious for a sinonasal tumor requires a thorough neurologic, ophthalmologic, and head and neck examination.

Computed tomography (CT) scan:

Radiographic assessment of esthesioneuroblastoma begins with a contrast-enhanced computed tomography (CT) scan. Sinus disease and bony erosion depict well with CT scans.[8]

Magnetic resonance imaging:

Esthesioneuroblastoma is most typically hypointense compared with brain gray matter on T1-weighted MRI and should enhance with gadolinium. T2-weighted images show an isointense or hyperintense mass. MRI provides better discrimination between tumor and secretions and optimal evaluation of orbital and intracranial or brain parenchymal involvement.[8]

Nuclear medicine scan:[15]

Most of these tumors are MIBG-avid, which can be used to differentiate them from anterior cranial fossa meningiomas.

Biopsy of the tumor:

Intraoperative biopsy under general anesthesia for the sinonasal mass is recommended. The biopsy is preferably performed after imaging studies have been reviewed to determine the vascularity of the mass.[8]

Treatment / Management

The three options used for the treatment of esthesioneuroblastoma are surgery, external beam radiation, and chemotherapy. Often, the treatment utilizes a combination of these modalities.[8][16] For small tumors with no sign of regional or local metastasis, surgical resection is advocated.[8] More extensive surgery, typically an open or open or endoscopic-assisted craniofacial resection is recommended along with postoperative radiation therapy, as the disease becomes more locally advanced.[8][17] Preoperative radiation is an alternative strategy that may yield equivalent results, and induction chemotherapy, as well as concurrent postoperative chemoradiation, may improve local, regional, and distant control.[8] Patients with distant disease can have palliative therapy. Chemoradiation is an approach for patients with unresectable local disease, which could subsequently improve the resectability for locally-advanced esthesioneuroblastoma.[8][18](B2)

Differential Diagnosis

Malignant neoplasms[8]:

• Extramedullary plasmacytoma
• Extraosseous Ewing sarcoma/Primitive neuroectodermal tumor (PNET)
• Mesenchymal chondrosarcoma
• Natural killer/T-cell lymphoma
• Rhabdomyosarcoma
• Sinonasal malignant melanoma
• Sinonasal neuroendocrine carcinoma
• Sinonasal undifferentiated carcinoma
• Small cell osteosarcoma
• Small cell undifferentiated (neuroendocrine) carcinoma
• Synovial sarcoma
• Undifferentiated (lymphoepithelioma like) carcinoma

Staging

Hyams et al. developed the most widely used grading system for esthesioneuroblastoma.[13] This system divides the spectrum of esthesioneuroblastoma maturation into four grades, ranging from most differentiated (grade I) to least differentiated (grade IV), based on tumor architecture, mitotic activity, nuclear pleomorphism, fibrillary matrix and rosettes, necrosis, gland proliferation, and calcifications. This grading scheme had independent validation relative to prognosis.[13][19]

The Kadish staging system is an effective means to predict disease-free survival and is widely accepted. It includes the following groups:

• Group A tumors: are limited to the nasal cavity
• Group B tumors: extend only to the paranasal sinus
• Group C tumors: extend beyond the nasal cavity and sinuses

A modified Kadish system includes group D tumors, which have distant metastasis or cervical lymphadenopathy.

Dulguerov also proposed a TNM (tumor/nodes/metastasis) style staging system allowing the inclusion of nodal status. This system was later reported to correlate closely with survival and recurrence.[20][21]

Prognosis

The prognosis of esthesioneuroblastoma is both stage- and grade-dependent. The 5-year survival of stage A tumors is 75% to 90% whereas stage C has a 45% survival. Likewise, high-grade tumors have a 25% 5-year survival whereas low-grade tumors have an 80% survival[8].  

Poor prognostic indicators of esthesioneuroblastoma include[8]: 

• Metastases
• High stage
• High-grade tumor
• Above 50 or below 20 or years of age at presentation
• Intracranial spread
• High proliferation
• Females
• Polyploidy/aneuploidy

Complications

Recurrence of esthesioneuroblastoma is common, usually occurs within 2 years of the initial presentation (about 30%). Metastasis develops in 35% of cases. The cervical lymph nodes are the most common site of spread. Distant metastasis occurs in approximately 10% of patients (lung, bone, liver, skin).[1]