—  SLIDE SEMINAR #10  —

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
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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) [1, 2] and mainly 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 [3, 4, 5, 6]. 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 hormone (ACTH) [7, 8] or antidiuretic hormone (ADH) [9, 10, 11]. 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 [12], squamous [13], teratomatous and rhabdomyoblastic differentiation [14] 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 [15], 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 [16, 17, 18]. 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 olfactory neuroblastoma [19, 20, 21, 22]. 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 [23]. On the contrary, small cell neuroendocrine carcinoma is a highly aggressive neoplasm with a poor prognosis [1, 24, 25] and median survival of only 14.5 months [26].

References:
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  2. 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.

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  9. 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.

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  11. 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.

  12. 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.

  13. 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.

  14. Slootweg, P. J. and Lubsen, H. Rhabdomyoblasts in olfactory neuroblastoma. Histopathology, 19: 182-184, 1991.

  15. 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.

  16. 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.

  17. 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.

  18. Mills, S. E. Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod Pathol, 15: 264-278, 2002.

  19. 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.

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 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.

  26. Galanis, E., Frytak, S., and Lloyd, R. V. Extrapulmonary small cell carcinoma. Cancer, 79: 1729-1736, 1997.