Esthesioneuroblastoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Esthesioneuroblastoma, also known as olfactory neuroblastoma, is a rare form of cancer involving nasal cavity and believed to arise from the olfactory epithelium. It can cause loss of vision, and taste.^[1] Esthesioneuroblastomas are undifferentiated tumors of neuroectodermal origin derived from the olfactory epithelium. The tumor cells are mitotically active and are the precursor cells that develop into sustentacular and neuronal cells. They usually present as a soft tissue mass in the superior olfactory recess involving the anterior and middle ethmoid air-cells on one side and extending through the cribriform plate into the anterior cranial fossa.^[2] Based on the duration of symptoms, esthesioneuroblastoma may be classified into two subtypes neuroblastoma proper and neuroendocrine carcinomas.^[3] Genes involved in the pathogenesis of esthesioneuroblastoma include chromosomal gains in 7q11 and 20q and deletions in 2q, 5q, 6p, 6q, and 18q. On gross pathology, soft and hemorrhagic, polypoid appearance, and rich and fragile vascular supply of the tumor are characteristic findings of esthesioneuroblastoma. On microscopic histopathological analysis, arrangements of cells into rosettes or pseudorosettes are characteristic findings of esthesioneuroblastoma.^{[4][5][6][7][8][9][10]} The incidence of esthesioneuroblastoma is approximately 0.4 per 100,000 individuals worldwide. Esthesioneuroblastoma can present in a wide range of age groups; however, it is mostly noted in a bimodal distribution, occurring most frequently in the second and sixth decades of life. There is no racial predilection to the esthesioneuroblastoma.^[11][4] There are no established risk factors for esthesioneuroblastoma. If left untreated, 10%-62% of patients with esthesioneuroblastoma may progress to develop metastasis. Common complications of esthesioneuroblastoma include tumor recurrence and metastasis. These tumors often display varying biologic activity ranging from indolent growth, with patient survival exceeding 20 years, to a highly aggressive neoplasm capable of rapid widespread metastasis, with survival limited to a few months. The five-year mortality rate of patients with esthesioneuroblastoma is approximately 56% and 20% for grade I and II and grade III and IV tumors, respectively. The ten-year mortality rate of patients with esthesioneuroblastoma is approximately 67% and 34% for grade I and II and grade III and IV tumors, respectively.^[12][11] Symptoms of esthesioneuroblastoma include nasal obstruction, epistaxis, ear pain, otitis media, hyposmia, nasal discharge, facial pain, changes in vision, lacrimation, facial numbness, and anosmia.^{[13][14][15][16][17]} Common physical examination findings of esthesioneuroblastoma include reddish-gray, polypoid mass located in the upper nasal fossa, epistaxis, nasal discharge, nasal pain, facial swelling, trismus, proptosis, diplopia, anosmia, serous otitis media, cervical lymphadenopathy, retropharyngeal lymphadenopathy, decreased visual acuity, extraocular movement paralysis, altered mental status, and frontal headaches. Biopsy may be helpful in the diagnosis of esthesioneuroblastoma. Findings on biopsy diagnostic of esthesioneuroblastoma include small, round-to-oval cells with coarsely granular chromatin, prominent nuclear membranes, multiple small nucleoli, and scant cytoplasm with pseudorosette or occasional Homer-Wright rosettes separated by fibrous septa. Calcification and necrosis are sometimes seen, and mitotic figures are rare.^[18] On head and neck CT, esthesioneuroblastoma is characterized by soft tissue attenuation, with relatively homogenous enhancement.^[4] Head and neck MRI scan is diagnostic of esthesioneuroblastoma. On head and neck MRI, esthesioneuroblastoma is characterized by heterogenous intermediate signal on T1 and T2weighted MRI and variable enhancement on T1 contrast with gadolinium.^[4] The predominant therapy for esthesioneuroblastoma is surgical resection followed by postoperative irradiation. Adjunctive radiation/chemotherapy may be required. The optimal therapy for esthesioneuroblastoma depends on the stage at diagnosis and regional or distant metastasis.^{[13][19][20][21][22][23][24][25][26]}

Esthesioneuroblastoma was first discovered by Berger and Luc, in 1924.^[27]

Based on the duration of symptoms, esthesioneuroblastoma may be classified into two subtypes neuroblastoma proper and neuroendocrine carcinomas.^[3]

Genes involved in the pathogenesis of esthesioneuroblastoma include chromosomal gains in 7q11 and 20q and deletions in 2q, 5q, 6p, 6q, and 18q. On gross pathology, soft and hemorrhagic, polypoid appearance, and rich and fragile vascular supply of the tumor are characteristic findings of esthesioneuroblastoma. On microscopic histopathological analysis, arrangements of cells into rosettes or pseudorosettes are characteristic findings of esthesioneuroblastoma.^{[4][5][28][7][8][9][10]}

Genes involved in the pathogenesis of esthesioneuroblastoma include chromosomal gains in 7q11 and 20q and deletions in 2q, 5q, 6p, 6q, and 18q.^[8][9][10]

Esthesioneuroblastoma must be differentiated from other tumors with similar histological appearance, such as lymphoma, Ewing sarcoma, melanoma, olfactory/ other (rhabdomyosarcoma or Merkel cell carcinoma), neuroblastoma, and small cell carcinoma. Distinguishing esthesioneuroblastomas from the other tumors is of paramount importance because the tumors respond differently to various treatment modalities.^[4][29]

The incidence of esthesioneuroblastoma is approximately 0.4 per 100,000 individuals worldwide. Esthesioneuroblastoma can present in a wide range of age groups; however, it is mostly noted in a bimodal distribution, occurring most frequently in the second and sixth decades of life. There is no racial predilection to the esthesioneuroblastoma.^[11][4]

There are no established risk factors for esthesioneuroblastoma.

According to the United States Preventive Services Task Force, screening for esthesioneuroblastoma is not recommended.^[30]

If left untreated, 10%-62% of patients with esthesioneuroblastoma may progress to develop metastasis. Common complications of esthesioneuroblastoma include tumor recurrence and metastasis. These tumors often display varying biologic activity ranging from indolent growth, with patient survival exceeding 20 years, to a highly aggressive neoplasm capable of rapid widespread metastasis, with survival limited to a few months. The five-year mortality rate of patients with esthesioneuroblastoma is approximately 56% and 20% for grade I and II and grade III and IV tumors, respectively. The ten-year mortality rate of patients with esthesioneuroblastoma is approximately 67% and 34% for grade I and II and grade III and IV tumors, respectively.^[31][11]

According to a staging system by Kadish, there are four stages of esthesioneuroblastoma based upon the extent of the primary tumor and lymph node or distant metastases. In 1992, Dulguerov and Calceterra proposed a classification based on the tumor, node, metastasis (TNM) system, predicted on CT and MRI findings that can be identified before treatment.^[32][33][34]

Symptoms of esthesioneuroblastoma include nasal obstruction, epistaxis, ear pain, otitis media, hyposmia, nasal discharge, facial pain, changes in vision, lacrimation, facial numbness, and anosmia.^{[13][14][15][16][17]}

Common physical examination findings of esthesioneuroblastoma include reddish-gray, polypoid mass located in the upper nasal fossa, epistaxis, nasal discharge, nasal pain, facial swelling, trismus, proptosis, diplopia, anosmia, serous otitis media, cervical lymphadenopathy, retropharyngeal lymphadenopathy, decreased visual acuity, extraocular movement paralysis, altered mental status, and frontal headaches.

Laboratory findings consistent with the diagnosis of [disease name] include hypercalcemia, syndrome of inappropriate antidiuretic hormone (SIADH), hyponatremia, and neurological paraneoplastic syndromes.

On head and neck CT, esthesioneuroblastoma is characterized by soft tissue attenuation, with relatively homogenous enhancement.^[4]

Head and neck MRI scan is diagnostic of esthesioneuroblastoma. On head and neck MRI, esthesioneuroblastoma is characterized by heterogenous intermediate signal on T1 and T2 weighted MRI and variable enhancement on T1 contrast with gadolinium.^[4]

Other imaging studies for esthesioneuroblastoma include angiography/digital subtraction angiography, nuclear medicine, nasal endoscopy, and scintigraphy.^[4]

Biopsy may be helpful in the diagnosis of esthesioneuroblastoma. Findings on biopsy diagnostic of esthesioneuroblastoma include small, round-to-oval cells with coarsely granular chromatin, prominent nuclear membranes, multiple small nucleoli, and scant cytoplasm with pseudorosette or occasional Homer-Wright rosettes separated by fibrous septa. Calcification and necrosis are sometimes seen, and mitotic figures are rare.^[18]

The predominant therapy for esthesioneuroblastoma is surgical resection followed by postoperative irradiation. Adjunctive radiation/chemotherapy may be required. The optimal therapy for esthesioneuroblastoma depends on the stage at diagnosis and regional or distant metastasis.^{[13][19][20][21][22][23][24][25][26]}

Surgery followed by postoperative irradiation is the mainstay of treatment for esthesioneuroblastoma.^[21]

There are no primary preventive measures available for esthesioneuroblastoma.

Secondary prevention strategies following esthesioneuroblastoma include nasal irrigation with sterile isotonic sodium chloride begins within a few days after packing removal, removal of nasal crusting should be performed regularly during initial postoperative visits, and craniotomy sutures are removed 7-10 days after surgery.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Esthesioneuroblastoma was first discovered by Berger and Luc, in 1924.^[1]

Esthesioneuroblastoma was first discovered in 1924 by Berger and Luc.^[2][3] The disease was brought into prominence by the case of Chantal Sébire, who was suffering from the disease and ended her life after being denied euthanasia.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Based on the duration of symptoms, esthesioneuroblastoma may be classified into two subtypes: neuroblastoma proper and neuroendocrine carcinomas.^[1]

• Neuroblastoma proper
  • Neuroblastoma proper has a histologic presentation similar to that of peripheral neuroblastomas of childhood.
  • Esthesioneuroblastoma 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 between the cells.
  • Rosettes of the Homer-Wright type are present.
  • On electronic microscopy, there is the presence of a dendritic cytoplasmic process with accumulations of small core granules within the process.
  • Neuroblastomas proper contain fibrillary material.

• Neuroendocrine carcinomas
  • Neuroendocrine carcinoma is admixture with glands.
  • A neurofibrillary component is absent and the growth pattern is that of solid nests without rosettes.
  • Dense core granules similar to those of neuroblastomas are present in the cytoplasm and cytoplasmic extensions.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Genetic mutations involved in the pathogenesis of esthesioneuroblastoma include chromosomal gains in 7q11 and 20q and deletions in 2q, 5q, 6p, 6q, and 18q. On gross pathology, a soft, hemorrhagic, polypoid appearance, and rich, fragile vascular supply are characteristic findings of esthesioneuroblastoma. On microscopic histopathological analysis, arrangements of cells into rosettes or pseudorosettes are characteristic findings of esthesioneuroblastoma.^{[1][2][3][4][5][6][7]}

• On gross examination, biopsy material from olfactory neuroblastoma is soft and hemorrhagic.
• Resection specimens may show a polypoid appearance.
• The vascular supply of the tumor is rich and fragile, accounting for the hemorrhagic gross appearance.

• Olfactory neuroblastomas are of neural crest cell origin. They are multilobulated pink-grey tumors.
• On microscopic histopathologic analysis, there is variable differentiation, from well formed neural tissue to undifferentiated neuroblasts with pseudorosette formation.^[1][2]
• Microscopically, the tumor grows beneath the surface respiratory epithelium and may produce focal ulceration.
• Esthesioneuroblastomas (ENBs) can display various histologic presentations.
  • The hallmark of well-differentiated esthesioneuroblastoma is the arrangement of cells into rosettes or pseudorosettes.
  • True rosettes (Flexner-Wintersteiner rosettes) are a ring of columnar cells circumscribing a central oval-to-round space. They appear clear on traditional pathologic sections.
  • Pseudorosettes (Homer-Wright rosettes) are characterized by a looser arrangement and the presence of fibrillary material within the lumen.

• In low-grade or well-differentiated lesions, the growth pattern is lobulated with transitions into sheets or discrete nests of tumor cells, which are small and round with high nuclear cytoplasmic ratios.^[4][8]
• In well-differentiated tumors, the nuclei show uniform chromatin distribution with small unremarkable nucleoli. The nuclei become progressively more pleomorphic, with prominent nucleoli and coarse chromatin clumping, with increasing tumor grade. The stroma in well-differentiated tumors is distinctly fibrillary, reflecting the neuronal processes made by the tumor cells. This stroma decreases in quantity as the tumor becomes less well-differentiated. Mitoses and areas of necrosis also become more frequent with increasing tumor grade.
• In one-half of olfactory neuroblastomas, Homer Wright pseudorosettes, which are composed of tumor cells surrounding a center of pink fibrillary material are seen.
• In higher grade tumors, true (Flexner type) rosettes, composed of tumor cells surrounding a central lumen are seen.
• Vascular or lymphatic invasion, necrosis, and dystrophic calcification are more common with increasing tumor grade.
• A few admixed ganglion cells may be present, on rare instances.
• Electron microscopy of olfactory neuroblastomas demonstrates numerous axonal-type cytoplasmic processes, which contain neurotubules, neurofilaments, and dense-core neurosecretory granules (100 to 200 nm in diameter). The S100 immunoreactivity corresponds to Schwann cells enveloping axonal processes and cell bodies.^[4][8]

• A tool called array comparative genomic hybridization was applied to the analysis of esthesioneuroblastomas. Although many alterations were identified by this study, chromosomal gains in 7q11 and 20q and deletions in 2q, 5q, 6p, 6q, and 18q have been confirmed by at least two other studies.
• Although still investigational, the demonstration of human achaete-scute homologue HASH1 gene expression could become the diagnostic procedure of choice. The HASH1 gene is expressed in immature olfactory cells and is involved in olfactory neuronal differentiation; therefore, it could be useful in distinguishing esthesioneuroblastoma from other poorly differentiated small blue cell tumors.^[5][6][7]

The Hyams histologic grading system grades tumors from I to IV based upon pathologic features such as mitotic activity and necrosis.^[8]

The various features of histopathological grading according to Hyams is shown below in a tabular form:^[8]

• Esthesioneuroblastoma may be associated with Trisomy 8.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Genes involved in the pathogenesis of esthesioneuroblastoma include chromosomal gains in 7q11 and 20q and deletions in 2q, 5q, 6p, 6q, and 18q.^[1][2][3]

• A tool called array comparative genomic hybridization was applied to the analysis of esthesioneuroblastomass. Although many alterations were identified by this study, chromosomal gains in 7q11 and 20q and deletions in 2q, 5q, 6p, 6q, and 18q have been confirmed by at least two other studies.
• Although still investigational, the demonstration of human achaete-scute homologue HASH1 gene expression, could become the diagnostic procedure of choice. The HASH1 gene is expressed in immature olfactory cells and is involved in olfactory neuronal differentiation; therefore, it could be useful in distinguishing esthesioneuroblastoma from other poorly differentiated small blue cell tumors.^[1][2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Esthesioneuroblastoma must be differentiated from other tumors with similar histological appearance, such as lymphoma, Ewing sarcoma, melanoma, rhabdomyosarcoma or Merkel cell carcinoma, and small cell carcinoma. Distinguishing esthesioneuroblastomas from the other tumors is of paramount importance because the tumors respond differently to various treatment modalities.^[1][2]

The differential diagnosis of esthesioneuroblastoma includes the following:^[1][2]

• Olfactory neuroepithelioma
• Olfactory groove meningioma/haemangiopericytoma
• Sinonasal carcinoma (including SCC, minor salivary gland adenocarcinoma)
• Rhabdomyosarcoma
• Nasopharyngeal carcinoma
• Melanoma metastases
• Lymphoma
• Chordoma
• Juvenile nasopharyngeal angiofibroma
• Pituitary macroadenoma

The outcome of following diseases with various immunohistochemical tests is shown below in a tabular form:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

The incidence of esthesioneuroblastoma is approximately 0.4 per 100,000 individuals worldwide. Esthesioneuroblastoma can present in a wide range of age groups; however, it is mostly noted in a bimodal distribution, occurring most frequently in the second and sixth decades of life. There is no racial predilection to esthesioneuroblastoma.^[1][2] Males are more commonly affected with esthesioneuroblastoma than females. The male to female ratio is approximately 1.2 to 1.^[3][4][5][6]

Esthesioneuroblastoma is noted in 4 out of 10 million individuals, accounting for 5% of sinonasal and 3% of intracranial tumors.^[1] Approximately 1,000 cases have been identified since Berger and Luc described the first case in 1924.^[7] According to the BBC, only 201 cases of the disease have been recorded worldwide in the past two decades. A 1997 literature search identified 1,457 cases in the published literature since its discovery in 1924, however 487 were cited in more than one paper, bringing the total of reported cases to 945.^[8]

The incidence of esthesioneuroblastoma was estimated to be 0.4 cases per 100,000 individuals worldwide.

Esthesioneuroblastoma commonly affects individuals in a wide range of age groups (3-90 years of age). There is a bimodal peak of occurrence in the third and sixth decades of life. The majority of cases of esthesioneuroblastoma occur in patients between 40 and 70 years of age; the median age at diagnosis is 53 years.

There is no racial predilection to esthesioneuroblastoma.

Males are more commonly affected with esthesioneuroblastoma than females. The male to female ratio is approximately 1.2 to 1.^[3][4][5][6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

There are no established risk factors for esthesioneuroblastoma.

There are no established risk factors for esthesioneuroblastoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

According to the United States Preventive Services Task Force, screening for esthesioneuroblastoma is not recommended.^[1]

According to the United States Preventive Services Task Force, screening for esthesioneuroblastoma is not recommended.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

If left untreated, 10%-62% of patients with esthesioneuroblastoma may progress to develop metastasis. Common complications of esthesioneuroblastoma include tumor recurrence and metastasis. These tumors often display varying biologic activity ranging from indolent growth, with patient survival exceeding 20 years, to a highly aggressive neoplasm capable of rapid widespread metastasis, with survival limited to a few months. The five-year mortality rate of patients with esthesioneuroblastoma is approximately 56% and 20% for grade I and II and grade III and IV tumors, respectively. The ten-year mortality rate of patients with esthesioneuroblastoma is approximately 67% and 34% for grade I and II and grade III and IV tumors, respectively.^[1][2]

Esthesioneuroblastoma tumors display varying clinical behaviors ranging from indolent growth to highly aggressive invasion.^[1] The average delay between the appearance of the initial symptom and the diagnosis is six months, however diagnosis may be delayed for years in some cases. The delay is predictable because initial symptoms tend to be subtle and are frequently common, occurring also in nasal diseases, including allergic polypoid sinus disease or long-term rhinosinusitis.^[3] Clinical presentation is usually secondary to nasal stuffiness and rhinorrhea or epistaxis. Presentation is often delayed and symptoms may have been present for many months. Patients often present late with larger tumors which can extend into the intracranial compartment (25-30% at diagnosis) and usually result in anosmia. Despite aggressive therapy, esthesioneuroblastoma has been noted to have a high local recurrence rate of approximately 50–60% with 10–62% presenting as metastatic cases and 20–30% of those cases involving the CNS. Once esthesioneuroblastoma cells invade the cribriform plate, they may spread to the anterior skull base, extend to the leptomeninges or brain parenchyma and can lead to drop metastasis anywhere in central neural axis.^[2] Retropharyngeal lymph nodes are at risk for metastatic disease, however level II lymph nodes are most frequently involved.^[4] Cervical and retropharyngeal nodal metastases are present in 10-44% of cases at diagnosis.^[5]

• Tumor recurrence
• Metastasis^[2]

• The majority of studies have found a correlation between Hyams grade and prognosis.^[6][7][8][9]
• The prognosis depends on the magnitude of the disease on initial diagnosis.
• Esthesioneuroblastomas often display varying biologic activity ranging from indolent growth, with patient survival exceeding twenty years, to a highly aggressive neoplasm capable of rapid widespread metastasis, with survival limited to a few months.
• CNS metastasis is reported to have a survival expectancy of two years or less and is usually noted 0–10 years after the initial diagnosis.
• Spinal metastasis of esthesioneuroblastoma is rare with only 28 documented cases involving the spine, spinal cord, or leptomeninges.^[10]
• The metastatic rate of esthesioneuroblastoma has been estimated to range from 10 to 62 percent. The most common site of metastatic disease is the cervical lymph nodes but metastatic disease has been found in the parotid, long bones, meninges, breast, lung, prostate, abdominal viscera, and pelvis.
• The rate of local recurrence for this tumor after therapy is 57% with a survival rate of 56% at the end of five years.
• Prognostic factors must be considered when determining the best treatment for esthesioneuroblasstoma. Murakami et al. reported that histological tumor grade and complete surgical resection are the two most important prognostic factors. Hwang et al. emphasized the importance of diagnosing the disease in an early stage and regular radiologic followups to detect disease recurrence, to improve prognosis.^[2]

The relationship between grade of the tumor and ten-year survival is shown below in a tabular form:

The relationshiip between grade of the tumor and five-year survival is shown below in a tabular form:^[9]

The relationship between metastasis and five-year survival of the tumor is shown below in a tabular form:^[5]

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