Ectopic adrenocorticotropic hormone syndrome in patients with olfactory neuroblastoma.

Olfactory neuroblastomas rarely secrete adrenocorticotropic hormone, leading to ectopic adrenocorticotropic hormone syndrome. However, the prevalence, timing, and triggers of ectopic adrenocorticotropic hormone syndrome in patients with olfactory neuroblastomas remain unclear. This study aimed to investigate these factors and conduct a literature review. Fifteen patients with olfactory neuroblastomas who underwent surgery at our institution were included. The prevalence of ectopic adrenocorticotropic hormone syndrome development was assessed by evaluating adrenocorticotropic hormone expression using immunohistochemistry. Furthermore, 26 patients with olfactory neuroblastomas who developed ectopic adrenocorticotropic hormone syndrome from previous reports were reviewed. Among the 15 patients, three (20%) showed adrenocorticotropic hormone-positive tumor cells at the time of initial surgery, and two (13%) developed ectopic adrenocorticotropic hormone syndrome. The timing of developing ectopic adrenocorticotropic hormone syndrome was 2.5 and 10 years following the initial treatment of olfactory neuroblastoma. Based on the literature review, nine patients with recurrent and metastatic olfactory neuroblastoma developed ectopic adrenocorticotropic hormone syndrome after the initial surgery, of whom, three had confirmed disease after developing ectopic adrenocorticotropic hormone syndrome, three developed during disease progression, two developed after receiving chemotherapy, and one developed after undergoing a biopsy. The timing of ectopic adrenocorticotropic hormone syndrome was 2.5-15 years after initial treatment. Our study revealed that acknowledging olfactory neuroblastomas can manifest as ectopic adrenocorticotropic hormone syndrome with a certain low prevalence is crucial. Moreover, our study speculated that tumor stimulation, such as biopsy or chemotherapy, as well as disease progression, could trigger ectopic adrenocorticotropic hormone syndrome onset. Thus, olfactory neuroblastomas can develop into ectopic adrenocorticotropic hormone syndrome, even long after the initial treatment.

Recurrent Wnt Pathway and ARID1A Alterations in Sinonasal Olfactory Carcinoma.

Sinonasal tumors with neuroepithelial differentiation, defined by neuroectodermal elements reminiscent of olfactory neuroblastoma (ONB) and epithelial features such as keratin expression or gland formation, are a diagnostically challenging group that has never been formally included in sinonasal tumor classifications. Recently, we documented that most of these neuroepithelial neoplasms have distinctive histologic and immunohistochemical findings and proposed the term "olfactory carcinoma" to describe these tumors. However, the molecular characteristics of olfactory carcinoma have not yet been evaluated. In this study, we performed targeted molecular profiling of 23 sinonasal olfactory carcinomas to further clarify their pathogenesis and classification. All tumors included in this study were composed of high-grade neuroectodermal cells that were positive for pankeratin and at least 1 specific neuroendocrine marker. A significant subset of cases also displayed rosettes and neurofibrillary matrix, intermixed glands with variable cilia, peripheral p63/p40 expression, and S100 protein-positive sustentacular cells. Recurrent oncogenic molecular alterations were identified in 20 tumors, including Wnt pathway alterations affecting CTNNB1 (n = 8) and PPP2R1A (n = 2), ARID1A inactivation (n = 5), RUNX1 mutations (n = 3), and IDH2 hotspot mutations (n = 2). Overall, these findings do demonstrate the presence of recurrent molecular alterations in olfactory carcinoma, although this group of tumors does not appear to be defined by any single mutation. Minimal overlap with alterations previously reported in ONB also adds to histologic and immunohistochemical separation between ONB and olfactory carcinoma. Conversely, these molecular findings enhance the overlap between olfactory carcinoma and sinonasal neuroendocrine carcinomas. A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.

Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells.

Olfactory neuroblastoma (ONB, esthesioneuroblastoma) is a sinonasal cancer with an underdeveloped diagnostic toolkit, and is the subject of many incidents of tumor misclassification throughout the literature. Despite its name, connections between the cancer and normal cells of the olfactory epithelium have not been systematically explored and markers of olfactory epithelial cell types are not deployed in clinical practice. Here, we utilize an integrated human-mouse single-cell atlas of the nasal mucosa, including the olfactory epithelium, to identify transcriptomic programs that link ONB to a specific population of stem/progenitor cells known as olfactory epithelial globose basal cells (GBCs). Expression of a GBC transcription factor NEUROD1 distinguishes both low- and high-grade ONB from sinonasal undifferentiated carcinoma, a potential histologic mimic with a distinctly unfavorable prognosis. Furthermore, we identify a reproducible subpopulation of highly proliferative ONB cells expressing the GBC stemness marker EZH2, suggesting that EZH2 inhibition may play a role in the targeted treatment of ONB. Finally, we study the cellular states comprising ONB parenchyma using single-cell transcriptomics and identify evidence of a conserved GBC transcriptional regulatory circuit that governs divergent neuronal-versus-sustentacular differentiation. These results link ONB to a specific cell type for the first time and identify conserved developmental pathways within ONB that inform diagnostic, prognostic, and mechanistic investigation.

Transcription Factor Expression in Sinonasal Neuroendocrine Neoplasms and Olfactory Neuroblastoma (ONB): Hyams' Grades 1-3 ONBs Expand the Spectrum of SATB2 and GATA3-Positive Neoplasms.

Sinonasal neuroendocrine neoplasms (SN-NENs) are rare and mostly include neuroendocrine carcinoma (NEC), whereas neuroendocrine tumor (NET) is exceptional in this site. Olfactory neuroblastoma (ONB) is a malignant neuroectodermal neoplasm arising in the nasal cavity. Albeit crucial for correct patients' management, the distinction of high grade ONB from NEC is challenging and requires additional diagnostic markers. The transcription factor SATB2 has been recently introduced in routine diagnostics as an immunohistochemical marker of distal intestine differentiation. No specific data are available about SATB2 and GATA3 expression in SN-NENs. GATA3, SATB2, and, for comparison, CDX2 expression were investigated in a series of epithelial and non-epithelial SN-NENs. We collected 26 cases of ONB and 7 cases of epithelial SN-NENs diagnosed and treated in our Institution. ONBs were graded according to Hyams' system and epithelial NENs were reclassified into 5 NECs, 1 MiNEN, and 1 amphicrine carcinoma. Immunohistochemistry was performed using standard automated protocols. Hyams' grades 1-3 ONBs stained diffusely and intensely for SATB2, whereas grade 4 ONBs and NECs were globally negative. The non-neuroendocrine component of MiNEN and the amphicrine carcinoma were strongly positive. GATA3 was heterogeneously and unpredictably expressed in Hyams' grades 1-3 ONBs, whereas grade 4 ONBs and NECs were completely negative. CDX2 was negative in all cases. Our study identifies, for the first time, SATB2 and GATA3 expression as features of Hyams' grades 1-3 ONBs, expands the spectrum of SATB2 and GATA3-positive neoplasms, and suggests that Hyams' grade 4 ONBs are not only clinically but also biologically different from low graded ONBs.

SSTR2 Expression in Olfactory Neuroblastoma: Clinical and Therapeutic Implications.

Somatostatin receptor 2 (SSTR2) expression has previously been documented in olfactory neuroblastoma (ONB). Here, we fully characterize SSTR2 expression in ONB and correlate staining results with clinicopathologic parameters including Hyams grade. We also assess SSTR2 immunohistochemistry expression in various histologic mimics of ONB to assess its diagnostic functionality. 78 ONBs (51 primary biopsies/excisions and 27 recurrences/metastases) from 58 patients were stained for SSTR2. H-scores based on intensity (0-3 +) and percentage of tumor cells staining were assigned to all cases. 51 histologic mimics were stained and scored in an identical fashion. 77/78 (99%) ONB cases demonstrated SSTR2 staining (mean H-score: 189, range: 0-290). There were no significant differences in staining between primary tumors and recurrences/metastases (mean H-score: 185 vs 198). Primary low-grade ONB had somewhat stronger staining than high-grade tumors (mean H-score: 200 vs 174). SSTR2 expression had no prognostic value when considering disease-free or disease-specific survival. SSTR2 staining is significantly higher in ONB than its histologic mimics (mean H-score: 189 vs 12.9, p < 0.001) suggesting a potential use of the marker in diagnosis of ONB. In conclusion, SSTR2 is consistently expressed in ONB suggesting a role for somatostatin-analog based imaging and therapy in this disease. More generally, SSTR2 may be another marker of neuroendocrine differentiation in ONB.

68Ga-DOTATATE and 18F-FDG PET/CT for the Management of Esthesioneuroblastoma of the Sphenoclival Region.

We present a 48-year-old woman with an olfactory neuroblastoma who was referred for accurate staging using PET/CT. The Ga-DOTATATE PET/CT showed a 51 × 32-mm mass with an SUVmax of 7.59 in the sphenoidal sinuses, whereas radiotracer uptake on F-FDG PET/CT was similar to that of brain tissue. Ga-DOTATATE PET/CT might be especially useful in regions with difficult tumor visualization resulting from high background, such as brain tissue. The results of this case may suggest that somatostatin receptor imaging in patients with esthesioneuroblastoma may facilitate the potential application of radiotheranostic agents for the treatment of this aggressive subtype of tumors.

Efficacy of Peptide Receptor Radionuclide Therapy for Esthesioneuroblastoma.

Esthesioneuroblastoma is rare, with limited therapeutic options when unresectable or metastatic; however, expression of somatostatin receptors qualifies it for peptide receptor radionuclide therapy (PRRT). We report outcomes of PRRT in esthesioneuroblastoma from 2 referral centers. Methods: Using PRRT databases at 2 European Neuroendocrine Tumor Society Centers of Excellence, cases were sought between 2004 and 2018 of patients who had PRRT with recurrent or metastatic esthesioneuroblastoma deemed unsuitable for further conventional therapies. Evaluations of survival and of response using a composite reference standard were performed. Results: Of 7 patients, 4 had partial response, 2 had disease stabilization, and one had early progression. Possible side effects include worsening cerebrospinal fluid leaks. Median progression-free survival was 17 mo (range, 0-30 mo), and median overall survival was 32 mo (range, 4-53 mo). Conclusion: PRRT shows promising efficacy and moderate survival duration in unresectable locally advanced or metastatic esthesioneuroblastoma warranting larger cohort studies incorporating measures of quality of life.

Integrated Multi-omic Analysis of Esthesioneuroblastomas Identifies Two Subgroups Linked to Cell Ontogeny.

Esthesioneuroblastoma (ENB) is a rare cancer of the olfactory mucosa, with no established molecular stratification to date. We report similarities of ENB with tumors arising in the neural crest and perform integrative analysis of these tumors. We propose a molecular-based subtype classification of ENB as basal or neural, both of which have distinct pathological, transcriptomic, proteomic, and immune features. Among the basal subtype, we uncovered an IDH2 R172 mutant-enriched subgroup (∼35%) harboring a CpG island methylator phenotype reminiscent of IDH2 mutant gliomas. Compared with the basal ENB methylome, the neural ENB methylome shows genome-wide reprogramming with loss of DNA methylation at the enhancers of axonal guidance genes. Our study reveals insights into the molecular pathogenesis of ENB and provides classification information of potential therapeutic relevance.

Comprehensive molecular profiling of advanced/metastatic olfactory neuroblastomas.

Olfactory neuroblastoma (ONB) is a rare, locally aggressive, malignant neoplasm originating in the olfactory epithelium in the nasal vault. The recurrence rate of ONB remains high and there are no specific treatment guidelines for recurrent/metastatic ONBs. This study retrospectively evaluated 23 ONB samples profiled at Caris Life Sciences (Phoenix, Arizona) using DNA sequencing (Sanger/NGS [Illumina], n = 15) and gene fusions (Archer FusionPlex, n = 6), whole genome RNA microarray (HumanHT-12 v4 beadChip, Illumina, n = 4), gene copy number assays (chromogenic and fluorescent in situ hybridization), and immunohistochemistry. Mutations were detected in 63% ONBs including TP53, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, and SMAD4 genes. Twenty-one genes were over-expressed and 19 genes under-expressed by microarray assay. Some of the upregulated genes included CD24, SCG2, and IGFBP-2. None of the cases harbored copy number variations of EGFR, HER2 and cMET genes, and no gene fusions were identified. Multiple protein biomarkers of potential response or resistance to classic chemotherapy drugs were identified, such as low ERCC1 [cisplatin sensitivity in 10/12], high TOPO1 [irinotecan sensitivity in 12/19], high TUBB3 [vincristine resistance in 13/14], and high MRP1 [multidrug resistance in 6/6 cases]. None of the cases (0/10) were positive for PD-L1 in tumor cells. Overexpression of pNTRK was observed in 67% (4/6) of the cases without underlying genetic alterations. Molecular alterations detected in our study (e.g., Wnt and cKIT/PDGFRA pathways) are potentially treatable using novel therapeutic approaches. Identified protein biomarkers of response or resistance to classic chemotherapy could be useful in optimizing existing chemotherapy treatment(s) in ONBs.

The clinicopathological spectrum of olfactory neuroblastoma and sinonasal neuroendocrine neoplasms: Refinements in diagnostic criteria and impact of multimodal treatments on survival.

OBJECTIVES: To provide a comprehensive review of the clinical and histopathological features of olfactory neuroblastoma (ONB) and other sinonasal neuroendocrine neoplasms (NENs), in order to refine diagnostic criteria, analyze treatment outcomes, and identify prognostic factors. METHODS: Data from an Italian multi-institutional database were analyzed. Patients were treated surgically via a minimally-invasive endoscopic approach followed by adjuvant radiotherapy or radiochemotherapy. Neoadjuvant cisplatin/etoposide chemotherapy was administered in cases of poorly-differentiated tumors. A centralized pathology review was performed in all cases. Patients were prospectively observed for survival. Overall (OS) and Disease-free survival (DFS) estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Statistically significant variables were entered in a multivariate Cox regression model. RESULTS: 98 patients with a median follow-up of 53months were included. Morphology review and the incorporation of cytokeratin 8/18 in the immunohistochemical panel modified the final diagnosis in 8/98 (8.2%) cases. The neoplasms were ultimately classified into four groups with different immunohistochemical profiles and clinical behaviors: ONB in 67 cases (5-year-OS, 91.6%); NEC (poorly-differentiated neuroendocrine carcinoma) in 22 cases (5-year-OS, 42.6%); MiNEN (mixed neuroendocrine/non-neuroendocrine neoplasm) in five cases (5-year-OS, 0%,0/5 cases); and NET (well-differentiated neuroendocrine tumor) in four cases (5-year-OS, 50%, 2/4 cases). Hyams grade and Ki67 index were independent prognostic factors for ONB. Neoadjuvant chemotherapy appeared to be associated with improved OS and DFS for NEC, independent of other clinicopathological variables. CONCLUSIONS: Induction chemotherapy improves survival outcomes in patients affected by poorly-differentiated tumors. Recent advances in histopathological diagnosis, including CK8/18 staining, allow to plan the most appropriate range of multimodal treatments.

OTX1 and OTX2 as possible molecular markers of sinonasal carcinomas and olfactory neuroblastomas.

OTX Homeobox genes are involved in embryonic morphogenesis and in the development of olfactory epithelium in adult. Mutations occurring in the OTX genes are reported to be associated to tumorigenisis in human. No reports correlate the expression of OTX genes and neoplasms of the nasal cavity. Thus, through immunohistochemical and Real-time PCR analysis we investigated OTX1 and OTX2 expression in the more frequent types of nasal and sinonasal tumours. Variable expression of both genes were found in normal sinonasal mucosa and in tumours. Interestingly, no expression of both OTX genes were detected in sinonasal intestinal-type adenocarcinomas; only OTX1 was found in non-intestinal-type adenocarcinomas and OTX2 was selectively expressed in olfactory neuroblastomas. In conclusion, OTX1 and OTX2 genes might have a role in the pathogenesis of different types of sinonasal neoplasms.

Syndrome of inappropriate antidiuretic hormone secretion in a case of olfactory neuroblastoma without anti-diuretic hormone immunoreactivity: A case report and review of the literature.

Olfactory neuroblastoma (ONB) is a relatively rare nasal or paranasal malignant tumor. This tumor is rarely accompanied by paraneoplastic syndromes such as syndrome of inappropriate antidiuretic hormone secretion (SIADH). Here, we report a 31-year-old female with histologically confirmed ONB who had been diagnosed with SIADH three years prior. She was treated with surgery followed by concurrent chemoradiotherapy. SIADH resolved immediately after surgical tumor resection. Immunohistochemically, both biopsy and resected specimens from the nasal cavity had been negative for ADH. Although extremely rare, ONB may be associated with SIADH, and the possibility of this cancer should be taken into account during the follow-up of idiopathic SIADH.

Expression pattern of ISL-1, TTF-1 and PAX5 in olfactory neuroblastoma.

Olfactory neuroblastoma (ONB) is a rare neoplasm of the sinonasal area with neuroendocrine differentiation. ISL-1, TTF-1 and PAX5 are transcription factors that are frequently upregulated in tumors showing neuroendocrine differentiation. The aim of our study was to evaluate these markers in a group of ONBs. We included 11 ONBs from 4 large university hospitals. Immunohistochemical expression of TTF-1, PAX5 and ISL-1 was evaluated. TTF-1, ISL-1 and PAX5 were expressed in 3/11 cases (27.27%, h-score: 3-45), 7/11 cases (63.64%, h-score: 23-200), and in 3/11 cases (27.77%, h-score 3-85), respectively. The patient with the strongest PAX5 reactivity exhibited an aggressive clinical course with rapid dissemination to the spine and death shortly after the diagnosis. No significant correlation in the expression of PAX5 and TTF-1 ( = 0.43; p = 0.18) was observed. ISL-1 is widely expressed in tumors with neuroendocrine differentiation and therefore of limited value in their differential diagnosis. TTF-1 positivity does not exclude the diagnosis of primary ONB, although usually only a small percentage of cells are positive. PAX5 expression is infrequent (27.27%) in ONB; however, if present it can be associated with a very aggressive clinical course.

Microvessel density and Ki-67 labeling index in esthesioneuroblastoma: is there a prognostic role?

Esthesioneuroblastoma (ENB) is a malignant neuroectodermal tumor. Hyams grading has an established role in its prognostication. The importance of microvessel density (MVD) and Ki-67 labeling index (Ki-67 LI) is well studied in various tumors, but the same remains understated in ENB. The aims of the study were to estimate proliferation index and MVD in ENB and to correlate them with Hyams grade. Twenty-six ENB cases diagnosed over a period of 5 years were included. Hyams grade, MVD, and Ki-67 LI were evaluated for each of them. The cases were categorized as low (Hyams grades 1 and 2) and high (Hyams grades 3 and 4) grades. Microvessel density and Ki-67 LI were correlated with grade. The treatment response was analyzed in different grades. The commonest histologic grade was 4 (42%). The mean Ki-67 LI was 2%, 8.2%, 30.8%, and 40.5% and mean MVD was 81.67/mm(2), 37/mm(2), 24/mm(2), and 25.2/mm(2) in grades 1, 2, 3, and 4, respectively. A statistically significant correlation of grade with Ki-67 LI (P < .001) and MVD (P < .007) was noted. Hyams grade in ENB correlates well with treatment response. Ki-67 LI is an important prognostic factor in ENB. We propose a cutoff of 25% for Ki-67 LI to differentiate low- vs high-grade ENB, but larger studies are needed for validation. Contrary to epithelial tumors, there is a decrease in MVD with increasing grade in ENB.

Intraoperative hypertensive crisis due to a catecholamine-secreting esthesioneuroblastoma.

BACKGROUND: Although uncommon, esthesioneuroblastomas may produce clinically significant amounts of catecholamines. METHODS: We report a patient with a catecholamine-secreting esthesioneuroblastoma who developed an intraoperative hypertensive crisis. RESULTS: A patient with a history of hypertension was referred to our skull base center for management of a residual esthesioneuroblastoma. A staged endonasal endoscopic approach was planned. At the conclusion of the first stage, a hypertensive crisis occurred. Workup revealed elevated levels of serum and urinary catecholamines. The patient was treated with alpha adrenoceptor blockade before the second stage. Serum catecholamine levels after this second stage were normal. On immunohistochemical analysis, the tumor cells were found to be positive for tyrosine hydroxylase, the rate limiting enzyme in catecholamine synthesis, and achaete-scute homologue 1, a transcription factor essential in the development of olfactory and sympathetic neurons. CONCLUSION: Catecholamine production should be considered in the differential of unexpected extreme hypertension during surgical resection of esthesioneuroblastoma.

Olfactory neuroblastoma in dogs and cats--a histological and immunohistochemical analysis.

Olfactory neuroblastoma (ONB) was identified in 13 dogs and nine cats. The tumours were subjected to microscopical examination and were graded using a human pathological grading system. In the canine and feline tumours there was more necrosis and higher mitotic activity (mitotic index and Ki67 labelling index) than reported in human ONB. Rosettes were a common feature of feline ONBs. A significant correlation was observed between the histological grade and the Ki67 labelling index. The histopathological diagnosis of ONB was confirmed immunohistochemically by demonstration of the neuronal marker neuron-specific enolase (NSE). Two other neuron-specific antibodies specific for microtubule-associated protein-2 (MAP-2) and neuronal nuclei antigen (NeuN) were evaluated. MAP-2 expression proved to have higher specificity than labelling for NSE. NeuN expression was less sensitive and of limited practical value.

Calretinin staining facilitates differentiation of olfactory neuroblastoma from other small round blue cell tumors in the sinonasal tract.

OBJECTIVE: Olfactory neuroblastoma (ONB) is an uncommon malignant tumor of the sinonasal tract and has a wide histologic differential diagnosis that includes other small round blue cell tumors (SRBCTs). Even with the use of immunohistochemistry (IHC), the correct diagnosis may be difficult, especially in small biopsies. The purpose of this study is to determine the usefulness of calretinin and p63 as an aid to distinguish ONB from other sinonasal SRBCTs. METHODS: IHC staining for calretinin and p63 was performed on 21 specimens diagnosed as ONB and on 42 other sinonasal SRBCTs. Specimens were retrieved from the files of the QEII HSC, Halifax and UHN, Toronto. RESULTS: All but 1 ONB (20 of 21) showed calretinin staining, with 15 of 21 showing staining in >75% of the tumor area and 18 of 21 showing moderate-to-strong staining intensity. Only pituitary adenomas (3 of 3) and a single case of small cell carcinoma, neuroendocrine type (1 of 2), showed a similar staining pattern. None of the ONBs showed staining for p63. P63 was positive in all cases of nonkeratinizing squamous cell carcinoma (2 of 2) and in single cases of mantle cell lymphoma (1 of 1) and poorly differentiated neuroendocrine carcinoma (1 of 1); however, it inconsistently stained diffuse large B-cell lymphoma (4 of 5), extranodal NK/T-cell lymphoma, nasal type (1 of 4), sinonasal undifferentiated carcinoma (1 of 6), and Ewing sarcoma/primitive neuroectodermal tumor (2 of 6). CONCLUSIONS: Calretinin appears to be a useful marker to distinguish ONBs from other SRBCTs of the sinonasal tract, particularly when staining is moderate/strong and extensive. The calretinin-positive, p63-negative phenotype is fairly specific for ONB. The addition of these 2 IHC stains may aid in the diagnosis of sinonasal SRBCTs that are poorly differentiated, have inconclusive conventional IHC, or are found in small biopsies.

Metastatic esthesioneuroblastoma secreting adrenocorticotropic hormone in pediatric patients.

The purpose of this article was to report a pediatric case of secondary cervical esthesioneuroblastoma involving the parapharyngeal lymph nodes. A 3-year-old boy came to our clinical observation because of a right lymphonodal mass evidenced by nuclear magnetic resonance and a diagnosis of Cushing syndrome associated with ectopic adrenocorticotropic hormone secretion, moon face, central obesity, asthenia, and hirsutism. At the age of 10 months, the patient underwent endoscopic surgery for asportation of the World Health Organization stage IV esthesioneuroblastoma. At 38 months of age, the patient underwent right parapharyngeal lymphadenectomy with surgical access by a double mandibulectomy. After surgery, serum ACTH, cortisolemia, and urinary excretion of cortisol were within the reference range. Blood pressure was recorded at 110/70 mm Hg. Moon face disappeared, as well as central obesity and hirsutism. Clinical report is presented together with brief review of literature.

Immunohistochemical characterization of human olfactory tissue.

OBJECTIVES/HYPOTHESIS: The pathophysiology underlying human olfactory disorders is poorly understood because biopsying the olfactory epithelium (OE) can be unrepresentative and extensive immunohistochemical analysis is lacking. Autopsy tissue enriches our grasp of normal and abnormal olfactory immunohistology and guides the sampling of the OE by biopsy. Furthermore, a comparison of the molecular phenotype of olfactory epithelial cells between rodents and humans will improve our ability to correlate human histopathology with olfactory dysfunction. STUDY DESIGN: An immunohistochemical analysis of human olfactory tissue using a comprehensive battery of proven antibodies. METHODS: Human olfactory mucosa obtained from 21 autopsy specimens was analyzed with immunohistochemistry. The position and extent of olfactory mucosa was assayed by staining whole mounts (WMs) with neuronal markers. Sections of the OE were analyzed with an extensive group of antibodies directed against cytoskeletal proteins and transcription factors, as were surgical specimens from an esthesioneuroblastoma. RESULTS: Neuron-rich epithelium is always found inferior to the cribriform plate, even at advanced age, despite the interruptions in the neuroepithelial sheet caused by patchy respiratory metaplasia. The pattern of immunostaining with our antibody panel identifies two distinct types of basal cell progenitors in human OE similar to rodents. The panel also clarifies the complex composition of esthesioneuroblastoma. CONCLUSIONS: The extent of human olfactory mucosa at autopsy can easily be delineated as a function of age and neurologic disease. The similarities in human versus rodent OE will enable us to translate knowledge from experimental animals to humans and will extend our understanding of human olfactory pathophysiology.