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Fig. 1.89 Olfactory neuroblastoma Grade III / IV. A Tumour nests comprised of cell and with nuclear pleo-morphism, increased mitotic activity and individual cell necrosis. B Higher magnification shows the presence of enlarged nuclei with moderate to marked pleomorphism, prominent nucleoli, absence of identifiable neurofibrillary matrix, and increased mitotic figures, including atypical mitoses. C The immunohistochem-ical antigenic profile typically shows absence of cytokeratin and presence of NSE. D S100 protein is limited to sustentacular cells along the periphery of the neoplastic lobules.

Fig. 1.89 Olfactory neuroblastoma Grade III / IV. A Tumour nests comprised of cell and with nuclear pleo-morphism, increased mitotic activity and individual cell necrosis. B Higher magnification shows the presence of enlarged nuclei with moderate to marked pleomorphism, prominent nucleoli, absence of identifiable neurofibrillary matrix, and increased mitotic figures, including atypical mitoses. C The immunohistochem-ical antigenic profile typically shows absence of cytokeratin and presence of NSE. D S100 protein is limited to sustentacular cells along the periphery of the neoplastic lobules.

protein staining typically is limited to the sustentacular cells situated along the periphery of the neoplastic lobules, although such cells may be sparse in the higher-grade tumours. In addition, immunoreactivity may be present for chromogranin, glial fibrillary acidic protein (GFAP), and Leu-7. Cytokeratin is usually negative, but some cases can show some positive cells. Epithelial markers, including epithelial membrane antigen (EMA) and carci-noembryonic antigen (CEA) are absent. Leucocyte common antigen (LCA), HMB-45, desmin and CD99 are absent. Proliferation marker studies using Ki-67 and MIB-1 have shown a high proliferative index of 10-50% and flow cytometric analysis shows frequent polyploidy/ane-uploidy {2560,2682}.

Electron microscopy

Electron microscopy evaluation is a useful adjunct in the diagnosis and includes the presence of dense core neurosecre-tory granules measuring 50-250 nm in diameter and neurite-like cell processes containing neurofilaments and neuro-tubules {1096,2567,2682}. In addition, Schwann-like cells and junctional complexes may be identified. When identified, olfactory rosettes show apical cilia with a 9 + 2 microtubule pattern, microvil-li, and junctional complexes.

Differential diagnosis

The differential diagnosis of olfactory neuroblastoma includes the group of small round cell malignant neoplasms that can occur in the sinonasal tract, i.e., sinonasal undifferentiated carcinoma, lymphoma, rhabdomyosarcoma, mucos-al malignant melanoma and neuroendocrine carcinomas. This discussion will be limited to neuroendocrine carcinomas; for the others the reader may refer to the specific sections detailing these specific tumour types. Neuroendocrine carcinomas (NEC) include, among different tumour types, the carcinoid tumour, atypical carcinoid tumour and small cell carcinoma. NEC of the sinonasal tract are extraordinarily rare, and in contrast to the larynx, the most common subtype is small cell carcinoma. By light microscopy, small cell carcinoma typically is a submucosal hypercellular proliferation growing in sheets, cords and ribbons; the distinct lobular pattern of olfactory neuroblas-toma is absent. The cells are small and hyperchromatic with oval to spindle-shaped nuclei, absent nucleoli and minimal cytoplasm. Cellular pleomorphism, high nuclear to cytoplasmic ratio, high mitotic activity, confluent necrotic areas and individual cell necrosis are readily apparent as well as lymphovascular and perineural invasion. Characteristically, crush artifacts of the neoplastic cells are seen. Squamous cell foci may occasionally be present; glandular or ductal differentiation is rarely seen. Although uncommon, neural-type rosettes similar to those seen in olfactory neuroblastoma can be seen in association with small cell carcinoma. The overall light microscopic findings should allow for differentiating small cell carcinoma from olfactory neu-roblastoma in most cases, but immuno-histochemical evaluation may be required in some cases. The immunohis-tohemical profile of small cell carcinoma includes variable reactivity for cytoker-atin, chromogranin, synaptophysin, neuron specific enolase (NSE), S-100 protein and thyroid transcription factor-1 (TTF-1). Cytokeratin reactivity may include a punctate paranuclear or globoid pattern. The tumour usually is negative for cytok-eratin, and the positive cases do not show a punctate paranuclear or globoid pattern. In contrast to olfactory neurob-lastoma, NSE reactivity in small cell carcinoma is more likely to be focal than diffusely positive, and the S100 protein staining, if present, is dispersed throughout the cellular proliferation and not limited to sustentacular cells. Olfactory neu-roblastoma is also negative for TTF-1.

Genetics

Studies on cytogenetic aberrations in olfactory neuroblastoma are sparse {2612,2521}. Studies have found partial gains of chromosome material on 8q, while the other findings are conflicting. Inclusion of olfactory neuroblastoma within the Ewing sarcoma family of tumours {2428} or the primitive neuroec-todermal tumours (PNET) {1865} has been proposed {2467} because of the identification, in certain cases, of translocation t(11:22), which is regarded as specific molecular abnormality for Ewing sarcoma {575}. Recent studies using immunohistochemistry, fluorescent in situ hybridization and reverse transcriptase PCR have failed to confirm this translocation in olfactory neuroblastoma {72, 1384,1709,2001}. Therefore, olfactory neuroblastoma should be considered an entity distinct from PNET and the Ewing sarcoma family of tumours.

Table 1.7 Clinical staging for olfactory neuroblastoma {663,1243}

Stage

Extent of Tumour

5-Year survival

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