Head and Neck Pathology
Moderators: Dr. Christina MacMillan and Dr. Nina Gale
Case 4 -
Olfactory Neuroblastoma with Glandular Differentiation
Dr. Loretta Tse
This tumor comprises lobules to sheets of small round tumor cells separated by rich network of thin
fibrovascular septa and focally associated with fibrillary matrix. Most tumor cells demonstrate small
round nuclei, scanty cytoplasm, conspicuous mitotic figures and apoptotic bodies. These findings are
typical for olfactory neuroblastoma. The uncommon findings for olfactory neuroblastoma are the presence
of many clusters of clear epithelioid tumor cells forming true glands with luminal mucin. The pale
epithelioid tumor cells exhibit bigger nuclei, granular chromatin and abundant pale cytoplasm.
Immunohistochemically, the small round tumor cells express synaptophysin. S100-positive sustentacular
cells are focally found at the periphery of some lobules. The epithelioid tumor cells and the glands,
but not the small round cells, are cytokeratin positive.
Case 4 - Slide 1
Diagnosis: Olfactory neuroblastoma with glandular differentiation
Olfactory neuroblastoma (ONB) is classified as a neuroectodermal tumor that is considered to be
derived from the neuroepithelial element of the olfactory membrane and neuroectodermal element of
olfactory placode. The tumors are found among patients with a wide age range (3-90)
arise from the cribriform plate, superior turbinate and superior one third of the nasal septum, although
rare cases of primary ONB in ectopic sites have been reported
Patients often present with long
standing symptoms of hemorrhage or obstruction such as epistaxis or nasal obstruction. Rarely, some
patients present with symptoms related to ectopic secretion of hormones such as adrenocorticotropic
or antidiuretic hormone (ADH)
Grossly, the tumor often presents as a
reddish polypoid vascularized tumor. Microscopically, the most common appearance is that of a
vascularized cellular tumor comprising nests to sheets of small round cells traversed by fibrovascular
septa in a fibrillary background. The tumor cells often exhibit round nuclei, scanty cytoplasm and
variable number of mitotic figures. Rosettes of Homer-Wright type or even Flexner Wintersteiner type can
be observed. Ganglion cells, melanin-containing cells and divergent differentiation such as glandular
teratomatous and rhabdomyoblastic differentiation  are seen in rare cases. Some
tumors demonstrate nests of epithelioid tumor cells with considerable amount of cytoplasm, leading to
confusion with neuroendocrine carcinoma. Immunohistochemically, olfactory neuroblastomas demonstrate
immunoreactivity with synaptophysin, neuron specific enolase (NSE), chromogranin and neurofilament
protein. Most tumor cells do not express cytokeratin, but some positive cells can be observed.
S100-positive sustentacular cells are often found at the periphery of the tumor lobules.
The morphology of this tumor raises the differential diagnosis of other small round cell tumors of the
sinonasal tract , in particular malignant lymphoma, small cell neuroendocrine carcinoma, Ewing
sarcoma/PNET and rhabdomyosarcoma. Immunohistochemical studies can easily distinguish olfactory
neuroblastoma from malignant lymphoma and rhabdomyosarcoma. Sinonasal Ewing sarcoma/PNETs are rare and
mainly found among children and young adults
Ewing sarcoma/PNET shares the appearance of ONB
with many small round tumor cells and rare rosette formation. Ewing sarcoma/PNET, however, lacks the
lobular architecture and richly vascularized background, but more often shows coagulative necrosis.
Expression of CD99 and EWS/FL1 gene fusion that characterize Ewing sarcoma/PNET, are not observed in
The one entity that sometimes raises controversy is the small cell
neuroendocrine carcinoma. Small cell neuroendocrine carcinomas in sinonasal tract are identical to
pulmonary small cell neuroendocrine carcinomas. Small cell neuroendocrine carcinoma lacks the lobular
growth pattern, the richly vascularized stroma and fibrillary background. Immunohistochemical studies
with neuroendocrine markers such as NSE, synaptophysin and chromogranin, however, cannot distinguish
olfactory neuroblastoma from small cell neuroendocrine carcinoma. S100 sometimes is more useful as small
cell neuroendocrine carcinoma, although can express S100, do not show S100-positive sustentacular cells.
Small cell neuroendocrine carcinomas more commonly express epithelial markers, but often in a paranuclear
dot-like pattern. Although some investigators have considered neuroendocrine carcinoma and olfactory
neuroblastoma represent a spectrum of differentiation but not two different tumor entities. Other
investigators and the author prefer to make distinction between small cell neuroendocrine carcinoma and
olfactory neuroblastoma as two different tumor types. Olfactory neuroblastoma can be treated with
complete surgical excision followed by radiotherapy. The five year survival rate ranges from 40% to 80%
depending on the tumor grading and staging . On the contrary, small cell neuroendocrine carcinoma is
a highly aggressive neoplasm with a poor prognosis
and median survival of only 14.5 months
- Perez-Ordonez, B., Caruana, S. M., Huvos, A. G., and Shah, J. P. Small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses. Hum Pathol, 29: 826-832, 1998.
- Wenig, B. M., Dulguerov, P., Kapadia, S. B., Prasad, M. L., Fanburg-Smith, J. C., and Thompson, L. D. R. Neuroectodermal Tumours. In: E. L. Barnes et al (ed.), Pathology and Genetics of Head and Neck Tumours, pp. 66-70. Lyon: IARCPress, 2005.
- Jugie, M., Marsot-Dupuch, K., Chabolle, F., Raveau, V., Levy, C., Brocheriou, C., and Tubiana, J. M. [Unusual localization of an olfactory esthesioneuroma]. Ann Radiol (Paris), 35: 477-482, 1992.
- Esposito, S., Bruni, P., Visca, T., Oddi, G., and Callovini, G. M. Primary intracranial esthesioneuroblastoma. Case report. J Neurosurg Sci, 29: 25-30, 1985.
- Chacko, G., Chandi, S. M., and Chandy, M. J. Primary sphenoid and petrous apex esthesioneuroblastoma: case report. Br J Neurosurg, 12: 264-266, 1998.
- Hamilton, A. E., Rubinstein, L. J., and Poole, G. J. Primary intracranial esthesioneuroblastoma, (olfactory neuroblastoma). J Neurosurg, 38: 548-556, 1973.
- Yu, J., Koch, C. A., Patsalides, A., Chang, R., Altemus, R. M., Nieman, L. K., and Pacak, K. Ectopic Cushing's syndrome caused by an esthesioneuroblastoma. Endocr Pract, 10: 119-124, 2004.
- Kanno, K., Morokuma, Y., Tateno, T., Hirono, Y., Taki, K., Osamura, R. Y., and Hirata, Y. Olfactory neuroblastoma causing ectopic ACTH syndrome. Endocr J, 52: 675-681, 2005.
- al Ahwal, M., Jha, N., Nabholtz, J. M., Hugh, J., Birchall, I., and Nguyen, G. K. Olfactory neuroblastoma: report of a case associated with inappropriate antidiuretic hormone secretion. J Otolaryngol, 23: 437-439, 1994.
- Myers, S. L., Hardy, D. A., Wiebe, C. B., and Shiffman, J. Olfactory neuroblastoma invading the oral cavity in a patient with inappropriate antidiuretic hormone secretion. Oral Surg Oral Med Oral Pathol, 77: 645-650, 1994.
- Vasan, N. R., Medina, J. E., Canfield, V. A., and Gillies, E. M. Sinonasal neuroendocrine carcinoma in association with SIADH. Head Neck, 26: 89-93, 2004.
- Miller, D. C., Goodman, M. L., Pilch, B. Z., Shi, S. R., Dickersin, G. R., Halpern, H., and Norris, C. M., Jr. Mixed olfactory neuroblastoma and carcinoma. A report of two cases. Cancer, 54: 2019-2028, 1984.
- Kleinschmidt-DeMasters, B. K., Pflaumer, S. M., Mulgrew, T. D., and Lillehei, K. O. Sinonasal teratocarcinosarcoma ("mixed olfactory neuroblastoma-craniopharyngioma") presenting with syndrome of inappropriate secretion of antidiuretic hormone. Clin Neuropathol, 19: 63-69, 2000.
- Slootweg, P. J. and Lubsen, H. Rhabdomyoblasts in olfactory neuroblastoma. Histopathology, 19: 182-184, 1991.
- Iezzoni, J. C. and Mills, S. E. "Undifferentiated" small round cell tumors of the sinonasal tract: differential diagnosis update. Am J Clin Pathol, 124 Suppl: S110-121, 2005.
- Rud, N. P., Reiman, H. M., Pritchard, D. J., Frassica, F. J., and Smithson, W. A. Extraosseous Ewing's sarcoma. A study of 42 cases. Cancer, 64: 1548-1553, 1989.
- Jurgens, H., Bier, V., Harms, D., Beck, J., Brandeis, W., Etspuler, G., Gadner, H., Schmidt, D., Treuner, J., Winkler, K., and et al. Malignant peripheral neuroectodermal tumors. A retrospective analysis of 42 patients. Cancer, 61: 349-357, 1988.
- Mills, S. E. Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod Pathol, 15: 264-278, 2002.
- Argani, P., Perez-Ordonez, B., Xiao, H., Caruana, S. M., Huvos, A. G., and Ladanyi, M. Olfactory neuroblastoma is not related to the Ewing family of tumors: absence of EWS/FLI1 gene fusion and MIC2 expression. Am J Surg Pathol, 22: 391-398, 1998.
- Mezzelani, A., Tornielli, S., Minoletti, F., Pierotti, M. A., Sozzi, G., and Pilotti, S. Esthesioneuroblastoma is not a member of the primitive peripheral neuroectodermal tumour-Ewing's group. Br J Cancer, 81: 586-591, 1999.
- Kumar, S., Perlman, E., Pack, S., Davis, M., Zhang, H., Meltzer, P., and Tsokos, M. Absence of EWS/FLI1 fusion in olfactory neuroblastomas indicates these tumors do not belong to the Ewing's sarcoma family. Hum Pathol, 30: 1356-1360, 1999.
- Devaney, K., Wenig, B. M., and Abbondanzo, S. L. Olfactory neuroblastoma and other round cell lesions of the sinonasal region. Mod Pathol, 9: 658-663, 1996.
- Perez-Ordonez, B. Neuroendocrine Tumours. In: E. L. Barnes et al (ed.), Pathology and Genetics of Head and Neck Tumours, pp. 26-27. Lyon: IARCPress, 2005.
- Babin, E., Rouleau, V., Vedrine, P. O., Toussaint, B., de Raucourt, D., Malard, O., Cosmidis, A., Makaeieff, M., and Dehesdin, D. Small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses. J Laryngol Otol, 120: 289-297, 2006.
- Rosenthal, D. I., Barker, J. L., Jr., El-Naggar, A. K., Glisson, B. S., Kies, M. S., Diaz, E. M., Jr., Clayman, G. L., Demonte, F., Selek, U., Morrison, W. H., Ang, K. K., Chao, K. S., and Garden, A. S. Sinonasal malignancies with neuroendocrine differentiation: patterns of failure according to histologic phenotype. Cancer, 101: 2567-2573, 2004.
- Galanis, E., Frytak, S., and Lloyd, R. V. Extrapulmonary small cell carcinoma. Cancer, 79: 1729-1736, 1997.