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.

Olfactory Neuroblastoma: Morphological Reappraisal and Molecular Insights with Quantum Leap in Clinical Perspectives.

PURPOSE OF REVIEW: The purpose of review is to provide a comprehensive review of the literature focusing on the recent advances in the diagnosis, molecular underpinning, and targeted therapy of olfactory neuroblastoma (ONB). RECENT FINDINGS: Studies focused on the molecular fingerprinting of ONB are critical to engage new promising treatment strategies. Molecular-based subtype classifications have been proposed (basal-like ONB and neural-like ONB) but are not widely used. The rationale for implementation of DNA methylation analysis and IDH2 sequencing in routine work-up for ONB is gaining recognition. Expression of somatostatin receptors (SSTR) in ONB open new avenues for both, diagnostic (especially metastatic disease) and new treatment protocols with somatostatin analogs. Olfactory carcinoma is proposed as a unifying diagnostic terminology pertinent to epithelial divergent differentiation in olfactory neuroblastoma. Molecular (genetic and epigenetic) efforts on olfactory neuroblastoma are promising; however further refinement is needed for employment of these biomarkers as clinical standard of care. Ongoing and future multi-institutional collaborative studies will contribute to further understanding of ONB biology and aid the development of targeted treatments for this disease.

Prognostic significance of PD-1, CTLA-4, CD4, and CD8 expression in olfactory neuroblastoma.

There are limited data regarding immune surveillance mechanisms in olfactory neuroblastoma. We investigated the expression of programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD4, and CD8 in olfactory neuroblastoma to identify potential therapeutic targets. Immunohistochemistry was used to detect PD-1 and CTLA-4 and measure the numbers of CD4+ and CD8+ T cells in 56 patients with olfactory neuroblastoma. The relationships between these molecules in tumor microenvironment, clinicopathological features, and survival were analyzed. The prevalence of PD-1 in Kadish C stage was 24.14%, significantly greater than in Kadish A and B stage. CD4+ T-cell and CD8+ T-cell levels correlated with higher Hyams histological grade and Kadish stage. In addition, PD-1 was related positively with CTLA-4, CD4+ T cells, and CD8+ T cells in olfactory neuroblastoma. Univariate survival analysis showed that higher PD-1 positivity, CD8+ T cells, and Hyams grade correlated with worse clinical outcome. Multivariate analysis showed that the expression of PD-1 was an independent parameter for poor prognosis. In conclusion, olfactory neuroblastoma with PD-1 expression had more aggressive clinicopathological features and worse prognosis. PD-1 may potentially predict the outcome of olfactory neuroblastoma patients.

Olfactory Neuroblastoma-A Challenging Fine Line between Metastasis and Hematology.

Developing in a limited space, rare tumors located at the nose and paranasal sinuses are sometimes difficult to diagnose due to their modest clinical presentation, which is uncorrelated with anatomopathological diversity. This limits the preoperative diagnosis without added immune histochemical study; for that reason, we present our experience with these tumors with the intention of raising awareness. The patient included in our study was investigated by our department through clinical and endoscopic examination, imaging investigations, and an anatomic-pathological study. The selected patient gave consent for participation and inclusion in this research study in compliance with the 1964 Declaration of Helsinki.

Evaluating the prognostic potential of the Ki67 proliferation index and tumour-infiltrating lymphocytes in olfactory neuroblastoma.

AIMS: Olfactory neuroblastomas (ONBs) are rare malignant tumours that arise in the nasal vault. To date, the Hyams grade remains the only widely used histological grading system. However, it is based only on morphological criteria, and has not been updated since 1988. The objective of this study was to explore the prognostic potential of the Ki67 proliferation index (PI) and tumour-infiltrating lymphocytes (TILs) in ONB. METHODS AND RESULTS: A retrospective study was conducted on a bicentric series of 45 cases. The Ki67 PI was determined by counting at least 1000 nuclei on whole slides. TILs were evaluated with CD20, CD4 and CD8 immunohistochemical markers on whole slides. In this series, Hyams grades I, II, III and IV accounted for 13.4%, 44.4%, 20% and 22.2% of all cases, respectively. The Ki67 PI ranged from 1 to 93; the Ki67 PI was significantly higher in Hyams grade III-IV ONBs than in Hyams grade I-II ONBs (P < 0.0001). A Ki67 PI of ≥25 was associated with poorer survival (P = 0.02). TILs were present in both stromal and intratumoral compartments, but were located predominantly in the stromal component of the tumour. The numbers of intratumoral CD8+ cells/mm2 and CD4+ cells/mm2 were greater in high-grade ONBs than in low-grade ONBs (P = 0.0015 and P = 0.043, respectively). The numbers of T cells/mm2 and B cells/mm2 were not associated with survival, but a CD4/CD8 ratio of >2 was significantly associated with shorter survival (P = 0.04). CONCLUSION: Our findings suggest that the Ki67 PI and TILs could be used as prognostic markers, as a potential alternative to the Hyams grade.

Olfactory Neuroblastoma.

PURPOSE OF REVIEW: To provide a comprehensive review of the literature focusing on the recent advances in the diagnosis and management of olfactory neuroblastoma. RECENT FINDINGS: Multimodality treatment is usually recommended for the majority of ONB cases. Recent advances in surgical approaches include the evolving role of endonasal endoscopic surgical resection and reconstruction. The introduction of new conformal radiation techniques has improved the outcomes and reduced treatment-related toxicity to important structures such as the eye and the brain. The role of neoadjuvant and adjuvant chemotherapy is yet to be defined. In the last two decades, there have been advances in surgical techniques with endoscopic approaches, either alone or in combination with craniotomy, gradually replacing the open traditional approaches. Prolonged surveillance is recommended for ONB due to late recurrences associated with that tumor. The role of chemotherapy and elective neck irradiation is still controversial and needs more studies to investigate their optimal role.

Intravoxel incoherent motion MRI for differentiating sinonasal small round cell malignant tumours (SRCMTs) from Non-SRCMTs: comparison and correlation with dynamic contrast-enhanced MRI.

AIM: To investigate the value of intravoxel incoherent motion (IVIM) in the differentiation of sinonasal small round cell malignant tumours (SRCMTs) from non-SRCMTs and to compare and correlate these results with those of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). MATERIALS AND METHODS: Ninety patients with histologically confirmed sinonasal malignant tumours (53 SRCMTs and 37 non-SRCMTs) who underwent conventional MRI, IVIM, and DCE-MRI before treatment were enrolled. The IVIM and DCE-MRI parameters were measured. Statistical analyses were performed using Student's t-tests, receiver operating characteristic (ROC) curve analyses, and Spearman's correlation coefficients. RESULTS: A lower pure diffusion coefficient (D) value and a higher pseudo-diffusion coefficient (D*) value were found in the sinonasal SRCMTs than in the non-SRCMTs (p<0.001 and p=0.011, respectively). Moreover, the mean extravascular extracellular space volume ratio (Ve) of the SRCMTs was significantly lower than that of the non-SRCMTs (p=0.020). ROC curve analysis showed that the diagnostic performance of D outperformed those of the other perfusion and diffusion parameters. A cut-off D value of 0.56 ×10-3 mm2/s yielded a sensitivity of 80.4%, a specificity of 75%, and an accuracy of 78.2%, with an AUC of 0.825. Significant but poor-to-fair correlations were found between the parameters from IVIM and DCE-MRI. CONCLUSIONS: The D and D* values of IVIM and the Ve value of DCE-MRI are helpful in distinguishing sinonasal SRCMTs from non-SRCMTs, with the D values having the best diagnostic efficiency.

Olfactory neuroblastoma: a single-center experience.

Olfactory neuroblastoma (ONB) is a potentially curable disease, despite being an aggressive malignancy with a poor natural history. Our goal was to evaluate management outcomes for patients with ONB treated at our institution. Our prospective database for brain tumors and the pathology registry of head and neck cancers at Oslo University Hospital were searched to identify all patients treated for ONB between 1998 and 2016. Variables extracted from these databases, supplemented by retrospective chart reviews, underwent thorough analysis. All cases were formally re-examined by a dedicated head and neck pathologist. Twenty patients were identified. Follow-up was 100%. Mean follow-up was 81.5 months for the entire cohort and 120.3 months for patients with no evidence of disease. Fourteen patients underwent treatment of choice including craniofacial resection (CFR) with or without radiotherapy (XRT). Six patients could only receive less extensive treatment; three patients underwent lateral rhinotomy (LR) with or without XRT after being deemed medically unsuitable for CFR, while another three patients received only supportive, non-surgical treatment (due to positive lymph node status in two and to extensive tumor size in one case). Overall and disease-specific survival rates were 100% after 10 years of follow-up when negative surgical margins were achieved by CFR. Positive margins were associated with poorer outcome with no patients surviving longer than 44 months. Long-term survival was also achieved in two cases among patients not eligible for CFR: one case after radical LR and one case after radio-chemotherapy. Advanced disease at presentation (tumor size ≥40 mm, Kadish grades C and D, or TNM IVa and IVb) and positive surgical margins were correlated to significantly dismal survival. Our study suggests that CFR with or without adjuvant XRT is safe and leads to excellent long-time overall and disease-specific survival. Negative surgical margins, tumor size <40 mm, Kadish stage A/B, and TNM stages I-III are independent prognostic predictors of outcome.

Remote orbital recurrence of olfactory neuroblastoma (esthesioneuroblastoma).

Olfactory neuroblastoma is a rare and often locally aggressive malignancy that invades the orbit via local destruction. It is known to recur in a delayed fashion, particularly to the neck lymph nodes. This is a case of a 65-year-old gentleman who presents with recurrence in the orbit and a neck lymph node 19 years after treatment for his initial disease. This report describes the longest known interval in orbital recurrence and should alert the monitoring physician that extreme delays in recurrence can occur.

Ectopic primary olfactory neuroblastoma of the maxillary sinus.

Olfactory neuroblastoma (ONB) is a rare malignant tumor. Although the vast majority of cases arise in the nasal cavity, ONB is rarely reported in ectopic locations. We report a case of ONB in the maxillary sinus. A 63-year-old woman presented with left-sided nasal obstruction and epistaxis. Magnetic resonance imaging showed a nonenhancing left maxillary sinus tumor. Histologic sections showed ONB, Hyams grade IV, invading bone, skeletal muscle, and adjacent fibroadipose tissue. It is essential to be accurate when diagnosing sinonasal tumors because the differential diagnosis is broad, and one must consider the possibility of ectopic ONB, although it is rare. The behavior of ONB and other neuroendocrine tumors of the sinonasal region is quite different, and there are varied approaches to treatment. Therefore, an accurate diagnosis as well as correct grade and stage must be assigned.

Multidisciplinary treatment of olfactory neuroblastoma: Patterns of failure and management of recurrence.

PURPOSE: Esthesioneuroblastoma is an uncommon malignancy of the head and neck for which there is no defined treatment protocol. The purpose of this study is to report our experience with the treatment and patterns of failure of this disease. METHODS AND MATERIALS: From 1994 to 2012, 37 previously unreported patients with esthesioneuroblastoma were evaluated, and 32 eventually treated for cure at 2 academic medical centers. All patients were staged with Kadish criteria. The mean and median follow-ups were 96.1 and 76.5 months respectively (range 6-240 months). RESULTS: The Kadish stage was A in 6 patients, B in 13 patients, and C in 13 patients. Four patients were initially treated with concurrent chemo-radiation therapy. Twenty-eight patients were treated with primary surgery. Two (2) underwent open medial maxillectomy and 26 underwent craniofacial resection (open - 17, endoscopic - 9). Three patients received curative surgical resection only. Seven patients failed either within the cranial axis or distantly, 6 of the 7 are dead of disease, 10-194 months following initial treatment. Six patients had isolated neck recurrences, 4/6 were salvaged with neck dissection and additional chemo-radiation and remain alive 30-194 months following initial treatment. Estimated overall survival rate at 10 years was 78% based on Kadish and T stages. CONCLUSION: In this retrospective analysis of 32 patients, Kadish stage C and stage T3/T4 tumors were associated with worse outcome. Total radiation dose of 60 Gy, margin status, patient age, were not found to have significant prognostic value.

Metastatic follicular thyroid carcinoma masquerading as olfactory neuroblastoma: with skull-base, cranium, paranasal sinus, lung, and diffuse bone metastases.

Skull-base metastasis is rarely reported in thyroid carcinoma. We are presenting an unusual interesting case mimicking metastatic renal cell carcinoma with intense clear cell morphology, the thyroid origin of which was detected via positron emission tomography/computerized tomography scan proposed by the oncology council, while we were monitoring the subject with the initial diagnosis of paranasal sinus tumor. A mass was detected in the left nasal cavity in the endoscopic examination of the 68-year-old female patient referred by the ophthalmology clinic with the preliminary diagnosis of retro-orbital tumor upon being admitted with proptosis. A soft tissue lesion at a size of 68 × 39 × 53 mm located intracranially was detected by the brain computerized tomography. The biopsy taken and the immunohistochemical results were not satisfactory. Intense fluorodeoxyglucose involvement was observed in both lobes of the thyroid gland at positron emission tomography/computerized tomography taken with the recommendation of the council. Moreover, hypermetabolic nodules were seen in both lung parenchyma areas, whereas intense hypermetabolic lytic lesions were observed in the skeletal system. Thyroglobulin and thyroid transcription factor 1 stains displayed a strong staining on paraffin block. On the basis of these characteristics, the case was regarded as compatible metastatic follicular thyroid carcinoma, with skull-base, cranial, retro-orbital, paranasal sinus, lung, and bone metastases. This case showed us that multidisciplinary work and assessment of the oncology council play a highly critical role in making the diagnosis and guiding the treatment.

Collision tumors of the paranasal region: presentation of two cases.

Collision tumors in the paranasal region are extremely rare with limited literature data. To the best of our knowledge, this is the first report of associations of squamous cell carcinoma-esthesioneuroblastoma and lymphoma-hemangiopericytoma in the paranasal region. Preoperatively, radiological and clinical findings should be evaluated carefully for the diagnosis and two or more biopsy specimens should be taken from different morphological parts of the lesions. Adjuvant therapy should be planned according to two different histologies and special importance should be given to the tumor which indicates the prognosis of the patient. A multidisciplinary approach is required for the management of synchronous malignancies.

Update on olfactory neuroblastoma.

Olfactory neuroblastomas are uncommon malignancies that arise from olfactory receptor cells located high in the nasal cavity. Accurate diagnosis plays a crucial role in determining clinical results and guiding treatment decisions. Diagnosis can be a major challenge for pathologists, especially when dealing with tumours with poor differentiation. The discovery of several molecular and immunohistochemical markers would help to overcome classification difficulties. Due to the paucity of large-scale studies, standardisation of diagnosis, treatment and prediction of outcome remains a challenge. Surgical resection by endoscopic techniques with the addition of postoperative irradiation is the treatment of choice. In addition, it is advisable to consider elective neck irradiation to minimise the risk of nodal recurrence. Molecular characterisation will help not only to make more accurate diagnoses but also to identify specific molecular targets that can be used to develop personalised treatment options tailored to each patient. The present review aims to summarise the current state of knowledge on histopathological diagnosis, the molecular biology and management of this disease.

Esthesioneuroblastoma as an unusual cause for dystopia.

Abstract Esthesioneuroblastoma, also known as olfactory neuroblastoma, is an uncommon malignant neoplasm arising from the olfactory epithelium in the roof of the nasal cavity. There are very few case reports published worldwide. The common presenting symptoms of Esthesioneuroblastoma are unilateral nasal obstruction (70%), epistaxis (50%), anosmia, rhinorrhoea, facial pain, headache, excessive lacrimation and rarely proptosis and visual disturbance. Apart from being locally aggressive, it metastasizes by haematogenous and lymphatic routes. We report an extremely rare case of esthesioneuroblastoma in a 20-year-old man with orbital involvement presenting as dystopia. This rare tumour should be considered in the differential diagnosis for young patients presenting to ophthalmic outpatient department with dystopia.