Esthesioneuroblastoma

Etiology

The exact etiology of esthesioneuroblastoma is still unknown, and no definitive predisposing factors have been identified. The cell of origin remains uncertain. Proposed sources have included the olfactory neuroepithelium, ectodermal olfactory placode, the Jacobson vomeronasal organ, the Loci ganglion, the sphenopalatine ganglion, and the autonomic ganglia within the nasal mucosa; however, available evidence most strongly supports origin from malignant transformation of basal progenitor cells of the olfactory epithelium (malignant globular basal cells).[3][4][5]

Genetic mutations involving tumor protein p53 (TP53), fibroblast growth factor receptor kinase (FRK), notch receptor 3 (NOTCH3), SMARCA4 (SWI/SNF protein family, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4), rearranged during transfection (RET), and CTCF (CCCTC-binding factor) have been identified in esthesioneuroblastomas.[6]

Epidemiology

Esthesioneuroblastoma accounts for 2% to 6% of nasal cavity and paranasal sinus cancer cases and 0.3% of all upper aerodigestive tract malignancies, and has an estimated incidence of 0.4 cases per 1 million people.[7] The reported incidence of esthesioneuroblastoma appears to have increased, possibly reflecting improved recognition and reporting. Esthesioneuroblastoma may occur at any age, although most patients present in adulthood. The age distribution has been described as bimodal, with peaks in the 20s and 60s.[8] Men and women are affected equally.[9] In children, it represents the most frequent malignancy of the nasal cavity.

Pathophysiology

Esthesioneuroblastoma is thought to arise from, or show differentiation toward, olfactory neuroepithelium. These cells are normally present in the superior nasal cavity, including the superior nasal septum, superior turbinate, nasal roof, and cribriform plate region of the ethmoid bone.

Molecular and Genetic Profile

Esthesioneuroblastoma exhibits numerous chromosomal copy-number gains and losses, but no consistent recurrent pattern has been established.[10][11] In 1 study, a deletion on chromosome 11 and a gain on chromosome 1p correlated with metastasis and a worse prognosis.[12] 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, GL1, and GL2 in 70%, 70%, and 65% of human esthesioneuroblastoma specimens, respectively, suggests that the sonic hedgehog (SHH) signaling pathway may be involved in the pathogenesis of this neoplasm.[13] Recent research has found expression of the OMP and RIC8B genes in esthesioneuroblastomas.[14]

More recent molecular studies suggest that esthesioneuroblastoma is biologically heterogeneous. DNA methylation and multiomic analyses have identified molecular subgroups and have also helped distinguish true olfactory neuroblastoma from mimics such as IDH2-mutant sinonasal carcinoma, SMARCB1-deficient sinonasal carcinoma, and other poorly differentiated sinonasal tumors.[14] At present, these molecular findings are most useful diagnostically and investigationally, and they have not yet replaced histology, immunohistochemistry, Hyams grading, and clinical staging in routine management.

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 hypervascular. 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 anterior cranial fossa.[15]

Macroscopic Examination

Low-grade esthesioneuroblastomas form submucosal, sharply demarcated nests, lobules, or sheets of cells, often separated by richly vascular or hyalinized fibrous stroma. Homer Wright pseudorosettes, with neoplastic cells arranged around a central, delicate fibrillary neural matrix or neuropil, 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 a fibrillary background composed of interdigitating neuronal processes, or neuropil. Higher-grade tumors show tumor necrosis, pleomorphism, increased mitotic activity, decreased or absent neuropil, and a less conspicuous 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 Homer Wright rosettes are nearly pathognomonic in the nasal cavity when accompanied by 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 be present in esthesioneuroblastoma.[15]

Histopathologic characteristics of esthesioneuroblastoma have been compiled into the Hyams grading system, which correlates with prognosis (see Image. Hyams Grading System for Esthesioneuroblastoma).[16] 

Immunohistochemical Profile

The typical immunohistochemical profile includes diffuse staining for neuron-specific enolase, synaptophysin, chromogranin A, CD56 (NCAM), and beta-III tubulin, as well as variable S100 protein reactivity, typically in a sustentacular pattern highlighting cells at the periphery of tumor nests; this pattern may be reduced or absent in higher-grade tumors.[17] INSM1 may also support neuroendocrine differentiation. SSTR2 expression has been described in esthesioneuroblastoma and may have diagnostic, imaging, and therapeutic implications in selected cases. Sustentacular cells may also be GFAP-positive. Calretinin staining (nuclear and cytoplasmic) has been reported in esthesioneuroblastoma but can also be seen in other sinonasal tumors.[18] As many as one-third of esthesioneuroblastomas may also stain focally for cytokeratin (CAM5.2, CK18). Negative markers include CD45RB, CD99, p63, and FLI1. Proliferation marker studies reveal a variable Ki-67 proliferation index (2%-50%), and BCL2 expression increases with tumor grade.[19][20]

History and Physical

Clinically, esthesioneuroblastoma often has a subtle presentation mimicking benign inflammatory or infectious sinonasal disease, and a delay in diagnosis is not uncommon. Nasal obstruction and epistaxis are typical early manifestations; however, other, more specific symptoms may occur depending on the tumor's location and extent.[21] Anosmia can precede the diagnosis of esthesioneuroblastoma by several years.[22] Other symptoms may relate to extension into the paranasal sinuses (facial swelling, medial canthus mass), the orbit (orbital pain, proptosis, epiphora, or visual disturbance), the anterior cranial fossa (headache), or, rarely, to inappropriate antidiuretic hormone secretion.

Initial history should focus on nasal breathing and olfactory symptoms, including the frequency, side, and nature of any rhinorrhea or epistaxis. Clear, positional rhinorrhea is more concerning for an occult cerebrospinal fluid (CSF) leak, whereas recurrent unilateral epistaxis is concerning for neoplasia. Seasonal, alternating, or environmental clear rhinorrhoea or nasal obstruction are more consistent with benign allergic rhinitis. A neurologic history should be obtained, including headache history, visual symptoms, facial pain or weakness, as well as a social and occupational history that could elucidate risk factors for other sinonasal tumors, including tobacco smoking and occupational exposure to wood dust, heavy metals, or aromatic amines.

The physical examination should begin with a head and neck exam, with particular attention to anterior rhinoscopy and a detailed cranial nerve examination. Nasal endoscopy and otoscopy should be performed, as the tumor may obstruct the Eustachian tube. A neck examination should assess for lymphadenopathy that could indicate metastasis.

Evaluation

A thorough physical examination and nasal endoscopic evaluation are essential initially and should be complemented by contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI).

CT Scan

Radiographic assessment of esthesioneuroblastoma typically begins with an IV contrast-enhanced computed tomography (CT) scan. Sinus involvement and bony erosion are well depicted on CT, which contributes to initial staging and surgical planning (Figure 2).[15][23][15]

MRI

Esthesioneuroblastoma is typically hypo- to isointense relative to brain gray matter on T1-weighted MRI and usually enhances after gadolinium administration. T2-weighted images show an isointense or hyperintense mass. MRI provides better discrimination between tumor and retained sinus secretions and is superior for evaluating orbital, dural, intracranial, and brain parenchymal involvement.[15] When intracranial extension is present, cysts at the brain-tumor interface may be seen, although this finding is not universal. A dumbbell-shaped transcibrosphenoidal extension is a characteristic imaging feature, but it is not pathognomonic (see Image. Esthesioneuroblastoma).

Nuclear Medicine Imaging

Most of these tumors are metaiodobenzylguanidine (MIBG)-avid, a feature that can help differentiate them from anterior cranial fossa meningiomas.[24] In routine practice, this is rarely required. Fluorodeoxyglucose positron emission tomography (FDG PET)-CT may be useful after histologic diagnosis to evaluate regional or distant metastasis and to assess suspected recurrence. However, esthesioneuroblastoma may show relatively lower FDG avidity than other aggressive sinonasal malignancies. Because many esthesioneuroblastomas express somatostatin receptors, somatostatin receptor imaging with gallium-68 DOTATATE PET-CT or PET-MRI is an emerging adjunct in selected cases, particularly for recurrent, metastatic, or treatment-planning scenarios.[25]

Tumor Biopsy

Endoscopic transnasal biopsy of the sinonasal mass is usually performed to confirm the histologic diagnosis. Biopsy should be performed after imaging studies have been reviewed to assess tumor vascularity, skull base involvement, and the possibility of alternative diagnoses such as vascular lesions or encephalocele.[15]

Treatment / Management

Three modalities are used for the treatment of esthesioneuroblastoma: surgery, external beam radiation, and chemotherapy. Often, the treatment utilizes a combination of these modalities, depending on tumor stage, grade, extent, and resectability.[15][26] (B2)

Surgical resection is advocated as the primary modality whenever possible.[15] This can involve 1 of 2 modalities, depending on the extent of the tumor: Endoscopic resection (usually through an endonasal approach) or open resection (via transfacial, transcranial, or combined craniofacial approaches, often in conjunction with a neurosurgeon).[15][27] Regardless of the resection modality, any resultant skull base defect must then be reconstructed. This can be accomplished with free grafts, such as fascia, bone, or cartilage, or vascularized flaps, such as a pericranial flap or nasoseptal flap.[28][29] The goal is to create a watertight seal to prevent CSF leakage, restore skull base continuity, support intracranial contents, and allow for subsequent radiation therapy.(B2)

Endoscopic craniofacial resection may be used for selected tumors involving the anterior skull base. The approach is tailored to the extent of the tumor and may include removal of the involved cribriform plate, fovea ethmoidalis, anterior skull base bone, and involved dura when required for complete oncologic resection. For tumors involving the frontal sinus or requiring wide access to the rostral anterior skull base, a Draf type III, or modified endoscopic Lothrop, frontal sinusotomy may be performed to create a common frontal sinus cavity and improve surgical exposure. Multilayer skull base reconstruction, often using fascia, fat, graft material, vascularized flaps, and sealant, is used to reduce the risk of postoperative CSF leak.

Orbital involvement should be assessed carefully during treatment planning. Limited periorbital or lacrimal sac involvement may be managed with orbit-preserving surgery and adjuvant therapy in selected patients, whereas extensive intraorbital involvement may require more aggressive treatment.

Many patients who undergo surgery for esthesioneuroblastoma benefit from postoperative radiation therapy, particularly those with higher-stage, higher-grade, margin-positive, or locally advanced disease. Combined surgical resection and postoperative radiation therapy is commonly regarded as the preferred approach for many patients and has been associated with improved local control and survival in retrospective series.[30] Radiation therapy can be delivered via external beam, often using intensity-modulated radiation therapy (IMRT), and proton therapy has become more widely available in recent years as well.[31][32] The advantages of IMRT and proton therapy include precise delivery of radiation to the tumor volume while sparing radiosensitive surrounding structures such as the eyes, optic apparatus, and brain.

Preoperative (neoadjuvant) radiation therapy is an alternative strategy that may yield comparable results in selected patients, particularly those with early-stage Kadish A or B tumors. However, some centers avoid it because it may complicate postoperative tumor-bed mapping (see Image. Kadish Staging for Esthesioneuroblastoma).[15][33][15]

Neoadjuvant chemotherapy may be employed for advanced-stage Kadish C or D tumors or tumors involving structures that cannot be safely resected, such as the optic chiasm or extensive brain parenchymal involvement. Preoperative chemotherapy may be used to reduce tumor volume and facilitate surgical resection while preserving critical structures, followed by surgery and adjuvant radiation therapy when feasible.[34][15][35]  Chemotherapy is typically platinum-based, commonly using cisplatin or carboplatin in combination with agents such as etoposide; other agents, including vincristine, doxorubicin, ifosfamide, and cyclophosphamide, have also been used.[36][37][38](B2)

The neck should be evaluated at initial presentation with clinical examination and imaging. Patients with clinically or radiologically evident cervical nodal disease are generally treated with neck dissection, radiation therapy, or both. In clinically node-negative patients, elective neck irradiation or elective neck dissection may be considered for higher-risk tumors, particularly Kadish C or D tumors, high Hyams grade tumors, or tumors with other adverse features; however, the benefit must be balanced against treatment-related morbidity.

Patients with recurrent or widely metastatic disease are candidates for palliative therapy. Depending on disease location, symptom burden, and prior treatment, palliation may include radiation therapy or chemotherapy, with chemotherapy most commonly used.[39][40][36](B3)

Long-term surveillance is required after definitive treatment because esthesioneuroblastoma may recur locally, regionally, or distantly many years after initial therapy. Follow-up generally includes regular nasal endoscopy, clinical examination of the neck, and interval MRI of the sinonasal tract and anterior skull base. Chest imaging or PET-CT may be considered when clinically indicated or in higher-risk disease. Surveillance should be extended beyond the first 5 years.

Differential Diagnosis

Differential diagnoses, particularly other sinonasal small round blue cell tumors and poorly differentiated malignancies, include:

• Extramedullary plasmacytoma
• Extraosseous Ewing sarcoma/Ewing sarcoma family tumor/primitive neuroectodermal tumor (PNET)
• Mesenchymal chondrosarcoma
• Extranodal NK/T-cell lymphoma, nasal type
• Rhabdomyosarcoma
• Sinonasal malignant melanoma
• Sinonasal neuroendocrine carcinoma, including small cell neuroendocrine carcinoma
• Sinonasal undifferentiated carcinoma
• NUT carcinoma
• SMARCB1-deficient sinonasal carcinoma
• SMARCA4-deficient sinonasal carcinoma
• Small cell osteosarcoma
• Synovial sarcoma
• Lymphoepithelial carcinoma [15]

Staging

Hyams et al developed the most widely used grading system for esthesioneuroblastoma (see Image. Hyams Grading System for Esthesioneuroblastoma).[21] This Hyams grading system divides the spectrum of esthesioneuroblastoma maturation into 4 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, glandular differentiation, and calcifications. This grading scheme has been independently validated as prognostically significant.[21][41]

The Kadish staging system is an effective means of predicting disease-free survival and is widely accepted (see Image. Kadish Staging for Esthesioneuroblastoma). This system includes the following groups:

• Group A tumors: limited to the nasal cavity
• Group B tumors: involve the nasal cavity and one or more paranasal sinuses
• Group C tumors: extend beyond the nasal cavity and sinuses, including extension to the orbit, skull base, or intracranial compartment

A modified Kadish system includes group D tumors, defined by cervical nodal or distant metastasis.

Dulguerov proposed a TNM-style staging system that incorporates local tumor extent, nodal disease, and distant metastasis. This system was later reported to correlate closely with survival and recurrence.[4][42]

Prognosis

The prognosis of esthesioneuroblastoma is stage- and grade-dependent. The 5-year survival of stage A tumors is 75% to 90%, whereas stage C has a 45% survival. Similarly, high-grade tumors have been associated with approximately 25% 5-year survival, whereas low-grade tumors have been associated with approximately 80% 5-year survival.[15]

There are several poor prognostic indicators of esthesioneuroblastoma.[15] They include the following: 

• Cervical nodal or distant metastasis
• Advanced Kadish or Dulguerov stage
• High-grade tumor
• Age above 50 or below 20 at presentation
• Intracranial spread
• Positive or close surgical margins
• High Ki-67 proliferation index
• Aneuploidy or other adverse cytogenetic features
• Angiopoietin-like 4 (ANGPTL4) expression [43]

Comparative analyses of staging and grading systems have shown variable prognostic performance. In 1 systematic review, predictive accuracy for overall survival was highest for the Kadish system, followed by the Hyams grading system and TNM-based staging.[44]

Complications

Complications of esthesioneuroblastoma may result from local tumor invasion, treatment, or recurrence. Tumor-related complications include anosmia, epistaxis, orbital invasion with proptosis or visual impairment, skull base erosion, intracranial extension, cranial neuropathy, cervical nodal metastasis, distant metastasis, and, rarely, paraneoplastic syndromes such as inappropriate antidiuretic hormone secretion. Treatment-related complications include CSF leak, meningitis, sinonasal crusting, anosmia, epiphora, visual injury, wound complications, osteoradionecrosis, radiation-induced optic neuropathy, hypopituitarism, neurocognitive effects, xerostomia, and chemotherapy-related toxicities.

Recurrence of esthesioneuroblastoma is common, with reported recurrence rates of approximately 30% to 60%, and may occur many years after initial treatment. Metastasis develops in 35% of cases. The cervical lymph nodes are the most common site of regional spread. Distant metastasis occurs in approximately 10% of patients, most commonly involving bone, lung, liver, or skin.[1]