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==Overview==
==Overview==
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.<ref name="radio"> Esthesioneuroblastoma. Radiopedia(2015) http://radiopaedia.org/articles/olfactory-neuroblastoma Accessed on January 25, 2016</ref><ref name="librepathology">  Esthesioneuroblastoma. Libre pathology(2015) http://librepathology.org/wiki/index.php/Olfactory_neuroblastoma Accessed on January 25, 2015</ref><ref>Hyams, V. J. (1988). Tumors of the upper respiratory tract and ear. Washington, D.C.: Armed Forces Institute of Pathology.</ref><ref name="pmid8630875">{{cite journal| author=Hirose T, Scheithauer BW, Lopes MB, Gerber HA, Altermatt HJ, Harner SG et al.| title=Olfactory neuroblastoma. An immunohistochemical, ultrastructural, and flow cytometric study. | journal=Cancer | year= 1995 | volume= 76 | issue= 1 | pages= 4-19 | pmid=8630875 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8630875  }} </ref><ref name="pmid18408657">{{cite journal| author=Guled M, Myllykangas S, Frierson HF, Mills SE, Knuutila S, Stelow EB| title=Array comparative genomic hybridization analysis of olfactory neuroblastoma. | journal=Mod Pathol | year= 2008 | volume= 21 | issue= 6 | pages= 770-8 | pmid=18408657 | doi=10.1038/modpathol.2008.57 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18408657  }} </ref><ref name="pmid15272537">{{cite journal| author=Mhawech P, Berczy M, Assaly M, Herrmann F, Bouzourene H, Allal AS et al.| title=Human achaete-scute homologue (hASH1) mRNA level as a diagnostic marker to distinguish esthesioneuroblastoma from poorly differentiated tumors arising in the sinonasal tract. | journal=Am J Clin Pathol | year= 2004 | volume= 122 | issue= 1 | pages= 100-5 | pmid=15272537 | doi=10.1309/QD0K-9Q1J-BH6B-5GQQ | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15272537  }} </ref><ref name="pmid8583243">{{cite journal| author=Carney ME, O'Reilly RC, Sholevar B, Buiakova OI, Lowry LD, Keane WM et al.| title=Expression of the human Achaete-scute 1 gene in olfactory neuroblastoma (esthesioneuroblastoma). | journal=J Neurooncol | year= 1995 | volume= 26 | issue= 1 | pages= 35-43 | pmid=8583243 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8583243  }} </ref>


==Pathophysiology==
==Pathophysiology==
Olfactory neuroblastomas are of neural crest cell origin 1. They are mulilobulated pink-grey tumors.
===Gross Pathology===
Histology demonstrates variable differentiation, from well formed neural tissue to undifferentiated neuroblasts with pseudorosette formation 2. It has been suggested that olfactory neuroblastoma is actually part of the Ewing sarcoma group of tumours, rather than being related to neuroblastoma.  
*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 multilobulated pink-grey tumors.  
*On microscopic histopathologic analysis, there is variable differentiation, from well formed neural tissue to undifferentiated neuroblasts with pseudorosette formation.<ref name="radio"> Esthesioneuroblastoma. Radiopedia(2015) http://radiopaedia.org/articles/olfactory-neuroblastoma Accessed on January 25, 2016</ref><ref name="librepathology">  Esthesioneuroblastoma. Libre pathology(2015) http://librepathology.org/wiki/index.php/Olfactory_neuroblastoma Accessed on January 25, 2015</ref>
*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.<ref name="pmid8630875">{{cite journal| author=Hirose T, Scheithauer BW, Lopes MB, Gerber HA, Altermatt HJ, Harner SG et al.| title=Olfactory neuroblastoma. An immunohistochemical, ultrastructural, and flow cytometric study. | journal=Cancer | year= 1995 | volume= 76 | issue= 1 | pages= 4-19 | pmid=8630875 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8630875  }} </ref><ref name=hhh>Hyams, V. J. (1988). Tumors of the upper respiratory tract and ear. Washington, D.C.: Armed Forces Institute of Pathology.</ref>
*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.<ref name="pmid8630875">{{cite journal| author=Hirose T, Scheithauer BW, Lopes MB, Gerber HA, Altermatt HJ, Harner SG et al.| title=Olfactory neuroblastoma. An immunohistochemical, ultrastructural, and flow cytometric study. | journal=Cancer | year= 1995 | volume= 76 | issue= 1 | pages= 4-19 | pmid=8630875 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8630875  }} </ref><ref name=hhh>Hyams, V. J. (1988). Tumors of the upper respiratory tract and ear. Washington, D.C.: Armed Forces Institute of Pathology.</ref>
 
==Genetics==
*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.<ref name="pmid18408657">{{cite journal| author=Guled M, Myllykangas S, Frierson HF, Mills SE, Knuutila S, Stelow EB| title=Array comparative genomic hybridization analysis of olfactory neuroblastoma. | journal=Mod Pathol | year= 2008 | volume= 21 | issue= 6 | pages= 770-8 | pmid=18408657 | doi=10.1038/modpathol.2008.57 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18408657  }} </ref><ref name="pmid15272537">{{cite journal| author=Mhawech P, Berczy M, Assaly M, Herrmann F, Bouzourene H, Allal AS et al.| title=Human achaete-scute homologue (hASH1) mRNA level as a diagnostic marker to distinguish esthesioneuroblastoma from poorly differentiated tumors arising in the sinonasal tract. | journal=Am J Clin Pathol | year= 2004 | volume= 122 | issue= 1 | pages= 100-5 | pmid=15272537 | doi=10.1309/QD0K-9Q1J-BH6B-5GQQ | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15272537  }} </ref><ref name="pmid8583243">{{cite journal| author=Carney ME, O'Reilly RC, Sholevar B, Buiakova OI, Lowry LD, Keane WM et al.| title=Expression of the human Achaete-scute 1 gene in olfactory neuroblastoma (esthesioneuroblastoma). | journal=J Neurooncol | year= 1995 | volume= 26 | issue= 1 | pages= 35-43 | pmid=8583243 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8583243  }} </ref>
 
 
The Hyams histologic grading system grades tumors from I to IV based upon pathologic features such as mitotic activity and necrosis.<ref name=hhh>Hyams, V. J. (1988). Tumors of the upper respiratory tract and ear. Washington, D.C.: Armed Forces Institute of Pathology.</ref>
 
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align=center
|valign=top|
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Grade}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Features}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
:Grade I
| style="padding: 5px 5px; background: #F5F5F5;" |
*Grade I tumors are characterized by a prominent fibrillary matrix, tumor cells with uniform nuclei, absent mitotic activity, and [[necrosis]].
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
:Grade II
| style="padding: 5px 5px; background: #F5F5F5;" |
*Grade II tumors have some fibrillary matrix and exhibit moderate nuclear pleomorphism with some mitotic activity. There is no [[necrosis]].
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
:Grade III
| style="padding: 5px 5px; background: #F5F5F5;" |
*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.
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Grade IV
| style="padding: 5px 5px; background: #F5F5F5;" |
*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:<ref name=hhh>Hyams, V. J. (1988). Tumors of the upper respiratory tract and ear. Washington, D.C.: Armed Forces Institute of Pathology.</ref>
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align=center
|valign=top|
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Grade}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Mitotic Index}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Nuclear Polymorphism}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Fibrillary Matrix}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Rosettes}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Necrosis}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Lobular Architecture Preservation}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
:Grade I
| style="padding: 5px 5px; background: #F5F5F5;" |
Zero
| style="padding: 5px 5px; background: #F5F5F5;" |
None
| style="padding: 5px 5px; background: #F5F5F5;" |
Prominent
| style="padding: 5px 5px; background: #F5F5F5;" |
Homer Wright Rosettes
| style="padding: 5px 5px; background: #F5F5F5;" |
None
| style="padding: 5px 5px; background: #F5F5F5;" |
+
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
:Grade II
| style="padding: 5px 5px; background: #F5F5F5;" |
Low
| style="padding: 5px 5px; background: #F5F5F5;" |
Low
| style="padding: 5px 5px; background: #F5F5F5;" |
Present
| style="padding: 5px 5px; background: #F5F5F5;" |
Homer Wright Rosettes
| style="padding: 5px 5px; background: #F5F5F5;" |
None
| style="padding: 5px 5px; background: #F5F5F5;" |
+
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
:Grade III
| style="padding: 5px 5px; background: #F5F5F5;" |
Moderate
| style="padding: 5px 5px; background: #F5F5F5;" |
Moderate
| style="padding: 5px 5px; background: #F5F5F5;" |
Low
| style="padding: 5px 5px; background: #F5F5F5;" |
Flexner-Wintersteiner rosettes
| style="padding: 5px 5px; background: #F5F5F5;" |
Rare
| style="padding: 5px 5px; background: #F5F5F5;" |
+/-
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Grade IV
| style="padding: 5px 5px; background: #F5F5F5;" |
High
| style="padding: 5px 5px; background: #F5F5F5;" |
High
| style="padding: 5px 5px; background: #F5F5F5;" |
Absent
| style="padding: 5px 5px; background: #F5F5F5;" |
None
| style="padding: 5px 5px; background: #F5F5F5;" |
Frequent
| style="padding: 5px 5px; background: #F5F5F5;" |
+/-
|-
|}
===Associated Conditions===
===Associated Conditions===
* Associated with [[Trisomy 8]].
*Esthesioneuroblastoma may be associated with [[Trisomy 8]].


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
{{Central nervous system tumors}}


[[Category:Disease]]
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Latest revision as of 23:18, 26 November 2017

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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

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]

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 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]

Genetics

  • 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]

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 some 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:[8]

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

  • Esthesioneuroblastoma may be associated with Trisomy 8.

References

  1. ↑ 1.0 1.1 Esthesioneuroblastoma. Radiopedia(2015) http://radiopaedia.org/articles/olfactory-neuroblastoma Accessed on January 25, 2016
  2. ↑ 2.0 2.1 Esthesioneuroblastoma. Libre pathology(2015) http://librepathology.org/wiki/index.php/Olfactory_neuroblastoma Accessed on January 25, 2015
  3. ↑ Hyams, V. J. (1988). Tumors of the upper respiratory tract and ear. Washington, D.C.: Armed Forces Institute of Pathology.
  4. ↑ 4.0 4.1 4.2 Hirose T, Scheithauer BW, Lopes MB, Gerber HA, Altermatt HJ, Harner SG; et al. (1995). "Olfactory neuroblastoma. An immunohistochemical, ultrastructural, and flow cytometric study". Cancer. 76 (1): 4–19. PMID 8630875.
  5. ↑ 5.0 5.1 Guled M, Myllykangas S, Frierson HF, Mills SE, Knuutila S, Stelow EB (2008). "Array comparative genomic hybridization analysis of olfactory neuroblastoma". Mod Pathol. 21 (6): 770–8. doi:10.1038/modpathol.2008.57. PMID 18408657.
  6. ↑ 6.0 6.1 Mhawech P, Berczy M, Assaly M, Herrmann F, Bouzourene H, Allal AS; et al. (2004). "Human achaete-scute homologue (hASH1) mRNA level as a diagnostic marker to distinguish esthesioneuroblastoma from poorly differentiated tumors arising in the sinonasal tract". Am J Clin Pathol. 122 (1): 100–5. doi:10.1309/QD0K-9Q1J-BH6B-5GQQ. PMID 15272537.
  7. ↑ 7.0 7.1 Carney ME, O'Reilly RC, Sholevar B, Buiakova OI, Lowry LD, Keane WM; et al. (1995). "Expression of the human Achaete-scute 1 gene in olfactory neuroblastoma (esthesioneuroblastoma)". J Neurooncol. 26 (1): 35–43. PMID 8583243.
  8. ↑ 8.0 8.1 8.2 8.3 Hyams, V. J. (1988). Tumors of the upper respiratory tract and ear. Washington, D.C.: Armed Forces Institute of Pathology.

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