Mouse (Mus musculus) heterozygous F1 p53(+/-) transgenic (C3H/HeNTac female inbred x
C57BL/6-Trp53tml Brd het N12 male inbred F1) approx 45 weeks age female.Mouse survived to terminal sacrifice in a 39-week study, with no clinical abnormalities noted.
The brain had a mass. No lesion was recorded grossly in the nasal cavities.
The nasal submucosa is greatly expanded by nests of tumor cells
sometimes forming rosettes along a basement membrane. The rosettes in some cases have a distinct lumen; others
contain fibrillar cytoplasmic processes suggestive of microvilli. Nests of cells also extend under the olfactory and
respiratory epithelium and in between Stenos and Bowmans glands along the turbinates and nasal septum. Tumor
cells and nests extend through the cribriform plate into the olfactory bulb, across the nasal septum, and into the
maxilla and periodontal space. Many tumor cells do not appear to rest upon a basement membrane. In several areas
tumor cells appear contiguous with olfactory epithelium and then extend beneath it. There is scant fibrovascular
Tumor cells are pleomorphic: those in rosettes tend to be elongate to triangular, with a wider base and scant cytoplasm; apical processes are sometimes present. The nuclei are basal, round to ellipsoid, with coarsely clumped chromatin or multiple nucleoli. There is a second population of tumor cells that is smaller and rounder, with very scant cytoplasm and multiple nucleoli; these are most often outside of the rosettes. The mitotic index is high (up to 25 mitotic figures per 0.238 mm2 high power field).
Adjacent to the main tumor mass, the architecture of many submucosal (Bowmans) glands is disorganized, with loss of cellular polarity and no apparent lumen. In some areas the cells are piled into more than one layer or even extend away from the basement membrane. These cells are enlarged and basophilic, with nuclei containing multiple nucleoli or coarsely-clumped chromatin. Although not nearly as common as in the main tumor mass, mitotic figures are not rare in these glands.
Cells in the overlying epithelium range from normal to containing eosinophilic granules, pyknotic nuclei or nuclear remnants, and lacking microvilli. There are intact neutrophils and nuclear remnants within the eosinophilic material (fluid) within the nasal cavities.
Neuroepithelial carcinoma (Esthesioneuroblastoma)
Ethesioneuroblastoma; Neuroepithelial carcinoma
The study pathologist received the brain sections before the nasal sections (since the
latter required time to decalcify) and made a tentative diagnosis of ependymoma (based upon the rosettes), although
the tumor morphology was not a good fit. On receipt of the nasal sections it became obvious the lesion in the brain
was an extension of a nasal esthesioneuroblastoma. This case illustrates the importance of keeping in mind
esthesioneuroblastoma (and other tumors of nasal origin) as a differential for large brain tumors that may appear to
originate in the rostral brain.
This tumor in the nasal sections is a good example of an esthesioneuroblastoma(1), with occasional true rosettes (Flexner-Wintersteiner rosettes) and more common pseudorosettes (Homer-Wright rosettes). This is an exceedingly rare tumor in mice, as in all mammals(2), and is likely present here in part because the strain is heterozygous for p53 gene knockout. The diagnosis in the brain was made more difficult as there the tumor adopted a solid sheet-type architecture, with only rare rosettes, a situation apparently typical of esthesioneuroblastomas in animals other than humans(2).
Olfactory bulb and nasal turbinates: Esthesioneuroblastoma.
Esthesioneuroblastomas, or olfactory neuroblastomas (ONB), arise from olfactory
neuroepithelium, residual neural crest cells, or local components of the dispersed neuroendocrine system and are
most often reported in dogs and cats. The olfactory epithelium contains three cell types, which can be histologically
identified in the tumor: basal cells, olfactory neurosensory cells, and supporting sustentacular cells. They arise in the
ethmoturbinate region and may penetrate the cribriform plate and infiltrate the cerebral cortex. ONBs may be
confused with lymphoma or undifferentiated carcinoma if important diagnostic features such as palisades around
blood vessels and rosette or pseudorosette formation are not present. ONBs are positive for synaptophysin,
chromogranin, CD56, neuron specific enolase (NSE), neural fibrillary protein (NFP) and S-100 protein(4).
Ultrastructural features include cytoplasmic membrane-bound dense core neurosecretory granules which contain neurotubules and neurofilaments. Olfactory differentiation with olfactory vesicles and microvilli or apical cilia on apical borders may be seen in Flexner-Wintersteiner rosettes. The fibrillary stroma corresponds to the immature nerve processes, and Schwann-like cells are uncommonly encountered(4,5).
The differential diagnosis of ONB includes the group of small round blue cell malignant neoplasms that can occur in the sinonasal tract, such as sinonasal undifferentiated carcinoma, extranodal NK/T cell lymphoma, rhabdomyosarcoma, Ewing/primitive neuroectodermal tumor (PNET), mucosal melanoma and neuroendocrine carcinomas (NEC)4. Other tumors considered in the differential diagnosis are paraganglioma, extramedullary plasmacytoma, pituitary adenoma, extracranial meningioma, mesenchymal chondrosarcoma, and granulocytic sarcoma. In cats, feline leukemia virus has been identified in association with olfactory neuroblastoma, but a causal role has not been established(3).
1. Maronpot RR, editor. Pathology of the Mouse. (1999). Cache River Press, Vienna, IL 62995.
2. Reznik GK, Schuller HM, & Stinson SF. Tumors of the nasal cavities, IARC Sci Publ. 1994;(111):305-24.
3. Schrenzel MD, Higgins RJ, Hinrichs SH, Smith MO, Torten M. Type C retroviral expression in spontaneous feline olfactory neuroblastomas. Acta Neuropathol. 1990;80(5):547-53.
4. Thompson LD. Olfactory neuroblastoma. Head Neck Pathol. 2009 Sep;3(3):252-9.
5. Wippold FJ 2nd, Perry A. Neuropathology for the neuroradiologist: rosettes and pseudorosettes. AJNR Am J Neuroradiol. 2006 Mar;27(3):488-92.