Molecular and phenotypic analysis of poorly differentiated sinonasal neoplasms: an integrated approach for early diagnosis and classification

Abstract

Accurate early diagnosis of poorly differentiated tumors of the sinonasal and skull-base sites is critical to modern multimodality management of patients with these tumors. A combined phenotypic and sequential biomarkers approach of a large retrospective cohort of these tumors led to the reclassification of some cases and the confirmation of uncertain diagnoses in others. An integrated algorithm of selected markers and phenotypic features for biopsy-based diagnosis of these tumors is presented and discussed. Primary poorly differentiated (small round and non-small) sinonasal neoplasms comprise histogenetically and biologically diverse entities with overlapping morphologic features. Because of the limited initial biopsy tissue materials, differential diagnostic difficulties may arise and complicate timely management of some cases. We employed immunohistochemical and molecular marker analyses in a large cohort of these tumors to optimize their early diagnosis and classification. Fifty-two tumors of the skull base and sinonasal regions and, for comparison, 19 poorly differentiated neoplasms of other head and neck sites were analyzed by a panel of immunohistochemical markers including those of epithelial, mesenchymal, melanocytic, and neuroectodermal origin using tissue microarray. RT-PCR analysis of mRNA for EWS-FLI1 and PAX-FKHR fusion transcripts and the hASH1 gene was performed on 24 of the 52 sinonasal tumors and the 19 tumors of other sites for comparison. The immunohistochemical results substantiated the phenotypic assessment and the initial diagnosis in 49 of the 52 tumors. In four instances the integrated markers and phenotypic analyses led to reclassification of three tumors and confirmed the histogenesis of a mesenchymal tumor with aberrant cytokeratin expression. Molecular analysis of the EWS-FLI1 fusion gene transcript revealed four (9.3%) of the 43 tumors to be positive; all were Ewing’s sarcomas. The hASH1 gene transcript was identified in 10 (23.8%) of 42 tumors: three of six neuroblastomas, all four neuroendocrine carcinomas, and one each in sinonasal undifferentiated carcinoma, rhabdomyosarcoma, and melanoma. The PAX-FKHR fusion transcript was not detected in any tumors. We conclude that 1) an integrated morphologic and biomarker algorithm may better optimize the early diagnosis of poorly differentiated sinonasal and skull-base tumors; 2) molecular analysis may assist in future biological stratification of certain classes of these tumors; and 3) the hASH1 gene transcript is a nonspecific marker for the diagnosis of neuroblastoma.

Ewing’s Family of Tumors of the Sinonasal Tract and Maxillary Bone

“…A total of 49 cases of proposed sinonasal EFT have been reported in the English language literature thus far [3,8,13,15,, 11 of which were confirmed with molecular studies [15,17,19,26,[37][38][39] and 21 of which have reported follow-up or outcomes [8, 13, 15, 19, 20, 22-26, 33, 35-37, 39, 40]. The pertinent information on previous cases of EFT with follow-up available is presented in Table 3.…”

“…The cases in this study were all considered diagnostic without molecular confirmation, although FISH or RT-PCR, was performed in 8 cases and shown to be positive. A recent study by Cordes et al demonstrated a EWSR1-FLI1 fusion transcript by RT-PCR on frozen tissue in only 4 of 10 cases of typical sinonasal EFT [17]. A negative RT-PCR study does not rule out alternative fusion gene partners for EWSR1, present in as much as 15% of EFT cases in other locations [1].…”

Ectopic Sphenoid Sinus Pituitary Adenoma (ESSPA) with Normal Anterior Pituitary Gland: A Clinicopathologic and Immunophenotypic Study of 32 Cases with a Comprehensive Review of the English Literature

“…Occasional cases may show neuroendocrine markers (such as chromogranin, synaptophysin, CD56 or CD57), but reactivity is usually weak and limited. Pituitary hormone and transcription factors are negative [63][64][65][66]. Again, the management with multimodality therapy is very different from the management for ESSPA, with a very different prognosis and outcome.…”

Small round blue cell tumors of the sinonasal tract: a differential diagnosis approach

“…38,39 Outcome and management. Rhabdomyosarcoma is considered a systemic disease, managed with multimodality therapies including surgery, chemotherapy and radiation, 40 frequently associated with adverse late sequela of treatment. 41 There is an overall poor prognosis of sinonasal tract alveolar rhabdomyosarcoma (5-year survival 30-40%), 29,35,[41][42][43][44] with patients frequently showing regional and/or distant metastases, although young patients (5-year survival 62.5%) tend to have a better prognosis.…”