- Author: Michael Somenek, MD; Chief Editor: Jules E Harris, MD, FACP, FRCPC more...
No specific lab studies confirm the diagnosis of esthesioneuroblastoma (ENB). Because surgery often is contemplated and because open nasal procedures are associated with significant bleeding and may involve blood transfusions, a complete blood count may be obtained, and the patient should be advised about preoperative blood donation.
Standard radiographs do not have a role in the evaluation of esthesioneuroblastoma (ENB). A direct coronal fine-cut (3 mm) CT scan is the initial radiologic study of choice.
ENB lacks a specific radiologic appearance and is seen as a homogeneous soft tissue mass with uniform and moderate contrast enhancement, as depicted in the 1st image above.
CT images are essential for correct staging and should be evaluated carefully for erosion of the lamina papyracea, cribriform plate, and fovea ethmoidalis specifically.
Obstruction of the sinus-draining ostia results in an accumulation of nasal secretions, which tend to be difficult to differentiate from tumor tissue when viewed on CT scan.
An unusual but characteristic imaging feature of ENBs is the presence of cysts at the tumor-brain interface. 
An example image is shown below.
Magnetic Resonance Imaging
MRI often is necessary to better delineate sinonasal and intraorbital extension or an intracerebral extension.
Using MRI, ENB appears as hypointense to gray matter on T1-weighted images and isointense or hyperintense to gray matter on T2-weighted images, as depicted in the second image above.
Because details of bony erosion are better demonstrated by CT images, both studies usually are required in the majority of patients.
An example image is shown below.
Since most ENBs express somatostatin receptors, the use of scintigraphy with a radiolabeled somatostatin analog (111 In-pentoctreotide [111 In-DTPA-D-pheoctreotide]; Octreoscan) has been proposed. A preliminary study of this technique found it to be clinically useful, especially for discriminating between postoperative changes and residual or recurrent tumor after extensive skull base surgery. The sensitivity and specificity remain unclear, however.
Esthesioneuroblastomas (ENBs) can display various histologic presentations. The hallmark of well-differentiated ENBs is arrangements of cells into rosettes or pseudorosettes (sheets and clusters). True rosettes (Flexner-Wintersteiner rosettes) refer to a ring of columnar cells circumscribing a central oval-to-round space, which appears clear on traditional pathologic sections. Pseudorosettes (Homer-Wright rosettes) are characterized by a looser arrangement and the presence of fibrillary material within the lumen.
One common method of stratification is to separate ENBs into 2 distinct groups: neuroblastomas proper and neuroendocrine carcinomas. The first group, neuroblastomas proper, has a histologic presentation similar to that of peripheral neuroblastomas of childhood. This group of ENBs is composed of sheets of poorly demarcated groups of cells separated by fine connective tissue trabeculae. The cells are small and typically show no mitotic activity. Importantly, these masses contain fibrillary material between the cells. Rosettes of the Homer-Wright type are present. One observed feature on electron microscopy is the presence of a dendritic cytoplasmic process with accumulations of small dense core granules within the process.
The unique feature of neuroendocrine carcinomas, the second class of ENBs, is admixture with glands. A neurofibrillary component is absent, and the growth pattern is that of solid nests without rosettes. In some cases, ENBs present as neoplastic cells that are intimately related to the basal epithelium of the glands, and a neurofibrillary component is not seen. The cells in these tumors are typically larger than those in neuroblastomas, and the growth pattern is that of solid nests without rosettes. Dense core granules similar to those of neuroblastoma are present in the cytoplasm and cytoplasmic extensions.
Further confounding accurate diagnosis is the fact that ENB is histologically similar to other small, round blue cell tumors. The acronym LEMONS ( lymphoma, Ewing sarcoma, melanoma, olfactory/ other [ENBs, rhabdomyosarcoma or Markel cell carcinoma], neuroblastoma, and small cell carcinoma) defines the other tumors from which ENB should be differentiated. Distinguishing ENBs from the other tumors is of paramount importance because the tumors respond differently to various treatment modalities.
The following list describes the outcome of each of these diseases with various
Esthesioneuroblastomas stain positive for S-100 protein and/or neuron-specific enolase, while the stain usually is negative for cytokeratin, desmin, vimentin, actin, glial fibrillary acidic protein, UMB 45, and the common leukocytic antigen. For difficult cases, electron microscopy can be useful. Common features are small, round neuroepithelial cells arranged in rosette or pseudorosette patterns, separated by fibrous elements. Rosettes consist of a central space ringed by columnar cells with radially oriented nuclei.
Lymphoma can be excluded when the majority of tumor cells are negative for CD45 (the remaining positive cells demonstrate no atypical immunophenotype).
Ewing sarcoma is positive for MIC2/CD99 gene products that result from an 11;22 translocation. 
Melanoma can be identified using a combination of immunohistochemical markers: MART-1/Melan-A, HMB-45, and S-100. S-100 is expressed in more than 95% of melanomas.
Rhabdomyosarcoma displays a loss of chromosome 11 and stains positive for desmin (expressed in 95%), muscle-specific actin, and myoglobin.
Markel cell carcinoma stains positively for low-molecular-weight cytokeratin 20 and NSE.
Neuroblastoma often stains positive for NSE, synaptophysin, Leu7, and neurofilament protein. Elevated serum catecholamines are also suggestive of neuroblastoma.
Small cell carcinomas stain positively for chromogranin, NSE, and synaptophysin (presynaptic nerve cell vesicles). Most small cell carcinomas are positive for TTF-1.
In summary, the pathologic distinction of poorly differentiated small neoplasms of the nasal cavity is difficult and is based on a panel of immunohistochemical stains and, if necessary, electron microscopy. To date, no specific immunocytologic stain identifies ENB; however, knowledge of the histochemistry of other related tumors can distinguish them. When ENB is suspected, diagnostic tests should include S-100 protein, neuron-specific enolase, chromogranin and/or synaptophysin, cytokeratin, desmin, actin, UMB 45, common leukocytic antigen, and myc-2 protein.
ENB can be graded histologically by the Hyams system, which is based on the preservation of lobular architecture, mitotic index, nuclear polymorphism, and the presence of fibrillary matrix, rosettes, and necrosis. The Hyams system is based on 4 grades, which are described in Table 1, below.
|Grade||Lobular Architecture Preservation||Mitotic Index||Nuclear Polymorphism||Fibrillary Matrix||Rosettes||Necrosis|
Tumor staging is an important guide for prognosis and therapy. Several staging systems, including Hymans (see Pathophysiology, above), Kadish, and TNM systems, have been proposed as a guide to choosing treatment modalities.
From a limited series of 17 patients, Kadish et al were the first to propose a staging classification for esthesioneuroblastoma (ENB). ENBs were divided into 3 categories: groups A, B, and C. Group A is limited to tumors of the nasal fossa; in group B, extension is to the paranasal sinuses; and group C is defined as extension beyond the paranasal sinuses and nasal cavity.
Some authors have noted that effectively stratifying patients with the Kadish system can be difficult. Recognizing these inadequacies, Morita et al in 1993 published a revised Kadish system that redefined stage C (consisting of local disease spreading beyond the paranasal sinuses) and included a stage D (distant metastasis).
In 1992, Dulguerov and Calceterra proposed a classification based on the tumor, node, metastasis (TNM) system, which is predicated on CT and MRI findings that can be identified before treatment. Although this classification system has gained popularity, attempts have been made to further modify the Kadish system for ENB.
The TNM classification is as follows:
T1 - Tumor involving the nasal cavity and/or paranasal sinuses (excluding sphenoid), sparing the most superior ethmoidal cells
T2 - Tumor involving the nasal cavity and/or paranasal sinuses (including the sphenoid), with extension to or erosion of the cribriform plate
T3 - Tumor extending into the orbit or protruding into the anterior cranial fossa, without dural invasion.
T4 - Tumor involving the brain
N0 - No cervical lymph node metastasis
N1 - Any form of cervical lymph node metastasis
M0 - No metastasis
M1 - Distant metastases present
Grossly, esthesioneuroblastoma (ENB) appears as a gray to red mass in the nasal vault. The color usually is related to the extent of tumor vascularization, raising the possibility of profuse nasal bleeding following the biopsy procedure.
Taking a biopsy specimen should be deferred until completion of the radiologic studies to avoid swelling effects on accurate imaging and the inadvertent biopsy of other nasal tumors of neurogenic origin.
Biopsy and endoscopy should be performed under general anesthesia. The specimen should be sent for regular staining, as well as for immunohistochemistry and possibly electron microscopy.
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|Grade||Lobular Architecture Preservation||Mitotic Index||Nuclear Polymorphism||Fibrillary Matrix||Rosettes||Necrosis|