Esthesioneuroblastoma pathophysiology

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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]

Overview

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.

Pathophysiology

Gross Pathology

• 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.

Microscopic Pathology

• Olfactory neuroblastomas are of neural crest cell origin. They are mulilobulated pink-grey tumors.
• Histology demonstrates variable differentiation, from well formed neural tissue to undifferentiated neuroblasts with pseudorosette formation.
• 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 arrangements of cells into rosettes or pseudorosettes.
  • 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.

• 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.
• 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.

Genetics

• 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.

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

Grade	Features
Grade I	Grade I tumors are characterized by a prominent fibrillary matrix, tumor cells with uniform nuclei, absent mitotic activity, and necrosis.
Grade II	Grade II tumors have some fibrillary matrix and exhibit moderate nuclear pleomorphism with son=me mitotic activity. There is no necrosis
Grade III	Grade III tumors have minimal fibrillary matrix and Flexner type rosettes are present. There is more prominent mitotic activity and nuclear pleomorphism, and some necrosis may be seen
Grade IV	Grade IV tumors have no fibrillary matrix or rosettes and show marked nuclear pleomorphism and increased mitotic activity with frequent necrosis

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

Grade	Mitotic Index	Nuclear Polymorphism	Fibrillary Matrix	Rosettes	Necrosis	Lobular Architecture Preservation
Grade I	Zero	None	Prominent	Homer Wright Rosettes	None	+
Grade II	Low	Low	Present	Homer Wright Rosettes	None	+
Grade III	Moderate	Moderate	Low	Flexner-Wintersteiner rosettes	Rare	+/-
Grade IV	High	High	Absent	None	Frequent	+/-

Associated Conditions

• Associated with Trisomy 8.