Intestinal-Type Adenocarcinoma in Head and Neck: Dissecting Oncogenic Gene Alterations Through Whole Transcriptome and Exome Analysis.

Adenocarcinomas of the nasal/paranasal sinuses are uncommon, but intestinal-type adenocarcinomas (ITACs) are important. Due to the rarity of these tumors, their molecular profile is not well known. To further investigate the molecular profile and find potential oncogenic drivers, we compared the whole transcriptome and exome of ITACs at different anatomic locations in the head and neck. Twenty-one head and neck adenocarcinomas were used in this study, divided into 10 sinonasal adenocarcinomas (SNT) and 11 extrasinonasal (T) head and neck adenocarcinomas according to anatomic location and histology. Tumor samples along with normal mucosa were microdissected from formalin-fixed, paraffin-embedded samples, and RNA and DNA were subjected to whole-transcriptome and -exome shotgun sequencing. Analysis of ITACs at sinonasal locations showed 410 subtype-specific differentially expressed (DE) genes and noncoding transcripts compared with the group of other anatomic locations, with 2909 subtype-specific DE genes. The groups shared 872 genes, with 17 highly different or opposing DE genes. Whole-exome mutation analysis revealed the gene MLL3 (KMT2C) to be exhibiting the most frequent loss-of-function mutations in all adenocarcinomas investigated. The results suggest that the head and neck ITACs investigated were mainly caused by loss-of-function mutations in MLL3 that disabled chromatin methylation and remodeling of all MLL3-targeted enhancers in the tumors. This changed the activity of multiple genes/gene clusters, supporting oncogenicity mostly via pathways of signaling, dedifferentiation, proliferation, migration, and immune and inflammatory deregulation, indicating a truly epigenetic event as the root cause for the heterogenous diversity of these enteric types of cancer. The data of this study form the basis for understanding cell fate determination and cellular homeostasis in the normal respiratory mucosa at different anatomic sites and show the contribution of different mucosal components to the etiology/molecular pathology of ITAC.

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.

FGFR1/2/3-rearranged carcinoma of the head and neck: expanded histological spectrum crossing path with high-risk HPV in the sinonasal tract.

AIMS: Oncogenic FGFR1/2/3 rearrangements are found in various cancers. Reported cases in head and neck (HN) are mainly squamous cell carcinomas (SCCs) with FGFR3::TACC3 fusions, a subset of which also harbour high-risk human papillomavirus (HPV). However, the knowledge of the clinicopathological spectrum of FGFR-rearranged head and neck carcinomas (FHNC) is limited. METHODS AND RESULTS: A retrospective MSK-fusion clinical sequencing cohort 2016-23 was searched to identify malignant tumours in the HN region harbouring FGFR1/2/3 fusion. FHNC were characterised by histological examination, immunohistochemistry and molecular analysis. Electronic medical records were reviewed. Three FHNC were identified. Two cases (cases 1 and 2) involved sinonasal tract and were high-grade carcinomas with squamous, basaloid, glandular and/or ductal-myoepithelial features. Case 1 arose in a 79-year-old man and harboured FGFR2::KIF1A fusion. Case 2 arose in a 58-year-old man, appeared as HPV-related multiphenotypic sinonasal carcinoma (HMSC), and was positive for FGFR2::TACC2 fusion and concurrent high-risk HPV, non-type 16/18. Case 3 was FGFR3::TACC3 fusion-positive keratinising SCCs arising in the parotid of a 60-year-old man. All three cases presented at stage T4. Clinical follow-up was available in two cases; case 1 remained disease-free for 41 months post-treatment and case 3 died of disease 2 months after the diagnosis. CONCLUSIONS: FHNC include a morphological spectrum of carcinomas with squamous features and may occur in different HN locations, such as parotid gland and the sinonasal tract. Sinonasal cases can harbour FGFR2 rearrangement with or without associated high-risk HPV. Timely recognition of FHNC could help select patients potentially amenable to targeted therapy with FGFR inhibitors. Further studies are needed (1) to determine if FGFR2 rearranged/HPV-positive sinonasal carcinomas are biologically distinct from HMSC, and (2) to elucidate the biological and clinical significance of FGFR2 rearrangement in the context of high-risk HPV.

Integrated Molecular and Histological Insights for Targeted Therapies in Mesenchymal Sinonasal Tract Tumors.

PURPOSE OF REVIEW: This review aims to provide a comprehensive overview of mesenchymal sinonasal tract tumors (STTs), a distinct subset of STTs. Despite their rarity, mesenchymal STTs represent a unique clinical challenge, characterized by their rarity, often slow progression, and frequently subtle or overlooked symptoms. The complex anatomy of the sinonasal area, which includes critical structures such as the orbit, brain, and cranial nerves, further complicates surgical treatment options. This underscores an urgent need for more advanced and specialized therapeutic approaches. RECENT FINDINGS: Advancements in molecular diagnostics, particularly in next-generation sequencing, have significantly enhanced our understanding of STTs. Consequently, the World Health Organization has updated its tumor classification to better reflect the distinct histological and molecular profiles of these tumors, as well as to categorize mesenchymal STTs with greater accuracy. The growing understanding of the molecular characteristics of mesenchymal STTs opens new possibilities for targeted therapeutic interventions, marking a significant shift in treatment paradigms. This review article concentrates on mesenchymal STTs, specifically addressing sinonasal tract angiofibroma, sinonasal glomangiopericytoma, biphenotypic sinonasal sarcoma, and skull base chordoma. These entities are marked by unique histopathological and molecular features, which challenge conventional treatment approaches and simultaneously open avenues for novel targeted therapies. Our discussion is geared towards delineating the molecular underpinnings of mesenchymal STTs, with the objective of enhancing therapeutic strategies and addressing the existing shortcomings in the management of these intricate tumors.

Endoscopy-assisted medial canthus incision for olfactory neuroblastoma: a case report.

Sinonasal malignant tumors are a group of uncommon malignancies that account for less than 1% of all tumors. These tumors often involve the maxillary sinus and nasal cavity, with less cumulative incidence in the ethmoidal sinus, sphenoidal sinus, and frontal sinus. The lack of consensus on the management of sinonasal malignancies is due to their rarity, diagnostic challenges, and the heterogeneity of treatments. In this paper, we present a case of endoscopic-assisted medial canthus incision combined with radiotherapy in the treatment of sinonasal malignant tumors, with the aim of providing valuable insights to clinicians on the management of these tumors.

Pneumocephalus with Inverted Papilloma in the Frontoethmoidal Sinus: Case Report and Literature Review.

Here, we describe the unique case of a pneumocephalus originating from an inverted papilloma (IP) in the frontoethmoidal sinus. A 71-year-old man with diabetes presented with headaches and altered consciousness. Imaging revealed the pneumocephalus together with bone destruction in the left frontal sinus. He underwent simultaneous endoscopic endonasal and transcranial surgery using an ORBEYE exoscope. Pathological diagnosis of the tumor confirmed IP. Post-surgery, the pneumocephalus was significantly resolved and the squamous cell carcinoma antigen level, which had been elevated, decreased. This case underscores the importance of a multidisciplinary approach and innovative surgical methods in treating complex sinonasal pathologies.

Surgical treatment of 186 sinonasal inverted papillomas and analysis of the immunohistochemical and molecular features associated with recurrences.

INTRODUCTION: Inverted papillomas (IP) are benign epithelial tumors with a tendency to be locally invasive and with disposition to recur. The aim of our study is to present the results of IP treatment, considering pathological, immunohistochemical and molecular features of recurrence. MATERIAL AND METHODS: From 1978 to 2020, 186 sinonasal IPs surgeries corresponding to 152 patients were treated in our center. We performed a pathology evaluation of all the recurrent cases reviewing the histological diagnosis, the presence of mixed component other than IP, the koilocytic changes, the p16 over expression and HPV-DNA detection. RESULTS: Overall recurrence rate was 19 % (35/186). The 35 IP recurrences correspond to 22 patients, 9 of whom presented a single recurrence (single recurrence group) while 13 of them presented more than one recurrence (multi-recurrent group). Immunohistochemical analysis showed a higher percentage of p16 overexpression (54 % vs 33 % p = 0.415) and HPV-DNA presence (23 % vs 0 % p = 0.240) in the multi-recurrent group compared with single recurrence group. In addition, the revision showed more IP with exophytic papilloma focus (38 vs 22 % p = 0.648) and a higher proportion of IP with koilocytotic changes (61 % vs 22 % p = 0.099) in the multirecurrent group. There is no significant difference between groups in our results. CONCLUSION: The analysis of our patients may differentiate between two groups with recurrent papillomas. A single recurrence group where the cause of recurrence is probably an anatomical problem related to an incomplete resection, and a second pattern, the multi-recurrence group, where HPV infection may be the main cause of recurrence.

Impact of facility volume on survival in primary endoscopic surgery for sinonasal squamous cell carcinoma.

OBJECTIVES: To evaluate the impact of facility volume on outcomes following primary endoscopic surgical management of sinonasal squamous cell carcinoma (SNSCC). METHODS: The 2010-2016 National Cancer DataBase (NCDB) was queried for patients diagnosed with T1-T4a SNSCC surgically treated endoscopically as the primary treatment modality. Factors associated with overall survival (OS) were evaluated, including facility volume. RESULTS: A total of 330 patients who underwent endoscopic surgical management of SNSCC were treated at 356 unique facilities designated as either low-volume (LVC; treating 1-2 cases; 0-75th percentile), intermediate-volume centers (IVC; 3-4 cases total; 75th-90th percentile), or 144 high-volume (HVC; treating 5+ cases total; >90th percentile) centers. HVC treated patients with higher T staging (42.1 % vs. 29.8 %) and tumors in the maxillary sinus (26.9 % vs. 13.2 %) and ethmoid sinus (10.3 % vs. ≤8.3 %), while LVCs treated lower T stage tumors (70.2 % vs. 57.9 %) and tumors that were located in the nasal cavity (70.2-78.5 % vs. 62.8 %). On multivariable analysis, factors associated with decreased OS included higher T stage (T3/T4a vs. T1/T2; OR 1.92, 95 % CI 1.06-3.47) and older age (>65 vs. <65; OR 2.69, 95 % CI 1.62-4.49). Cases treated at high-volume centers were not associated with a higher likelihood of OS when compared to low-volume centers (OR 0.70, 95 % CI 0.36-1.35). CONCLUSIONS: HVC are treating more primary tumors of the maxillary and ethmoid sinuses and tumors with higher T stages with endoscopic approaches, although this does not appear to be associated with increased OS. SHORT SUMMARY: Sinonasal squamous cell carcinoma (SNSCC) presents late in disease process with poor prognosis. We investigated the impact of facility volume on outcomes following endoscopic treatment of SNSCC. High-volume centers treat more advanced and complex disease with comparable OS.

Endoscopic resection of primary sinonasal mucosal melanoma with orbital invasion: How I do it.

Primary sinonasal mucosal melanoma is a rare aggressive malignancy. In this video, a case of a 68-year-old female who presented with diplopia for 2 weeks is described. The present video reports the endoscopic endonasal surgical excision of a primary sinonasal mucosal melanoma. The video contains patient's medical history, preoperative radiological evaluations and step-by-step description of surgical steps of the procedure with the utilization of computer-assisted navigation system.

Endoscopic management of sinonasal tumours in the Nordic university hospitals: a survey.

PURPOSE: The Nordic countries (27 M) all have comparable, publicly funded healthcare systems, and the management of sinonasal tumours is centralised to the 21 university hospitals. We sought to assess and compare the treatment practice of sinonasal tumours across the Nordic countries. METHODS: A web-based questionnaire was sent to all university hospital departments of otorhinolaryngology-head and neck surgery in the Nordic countries. RESULTS: Answers were obtained from all 21 Nordic university hospitals. The endoscopic approach was widely utilised by all, with most (62%) centres reporting 3-4 surgeons performing endoscopic sinonasal tumour surgery. Finland reported the lowest rates of centralisation among university hospitals despite having the highest number of 0.1-1 M catchment population hospitals. Most centres (88%) opted for the endoscopic approach in a patient case warranting medial maxillectomy. In a case of a Kadish C esthesioneuroblastoma, most (52%) of the centres preferred an endoscopic approach. Most centres (62%) reported favouring the endoscopic approach in a case describing a juvenile angiofibroma. Regarding a case describing a sinonasal undifferentiated carcinoma, consensus was tied (38% vs. 38%) between endoscopic resection followed by postoperative (chemo)radiotherapy (RT/CRT) and induction chemotherapy followed by RT/CRT or surgery followed by RT/CRT. CONCLUSION: Endoscopic approach was widely utilised in the Nordic countries. The case-based replies showed differences in treatment practice, both internationally and nationally. The rate of centralisation among university hospitals remains relatively low, despite the rarity of these tumours.

Therapeutic approaches to sinonasal NUT carcinoma: a systematic review.

PURPOSE: Sinonasal nuclear protein in testis carcinoma (SNUTC) is a rare, aggressive malignancy caused by genetic rearrangements in the NUTM1 gene. The prognosis of SNUTC ranks among the most unfavorable within the naso-sinusal district, with an overall survival of 9.7 months. This systematic review aimed to determine the best therapeutic strategy for SNUTC. METHODS: We reviewed eligible articles for patient demographics, TNM and stage at presentation, best response after primary treatment, disease-free survival and overall survival (OS) times, other following therapy lines, and final outcomes. RESULTS: Among 472 unique citations, 17 studies were considered eligible, with reported treatment data for 25 patients. Most studies (n = 12) were case reports. The most frequently administered treatment regimen was surgery as primary treatment and combined radiochemotherapy as second-line or adjuvant treatment. Four patients were alive at follow-up. CONCLUSION: Basing on the existing literature, a standardized line in the treatment of SNUTC is not yet well delineated. A self-personalized strategy of therapy should be drawn on each patient affected by SNUTC.

What is the rate of occult nodal metastasis in squamous cell carcinomas of the sinonasal tract? A systematic review.

OBJECTIVE: The role of elective neck dissection (END) in the management of clinical N0 (cN0) squamous cell carcinomas (SCC) of the sinonasal tract is unclear. In this systematic review, we evaluate the risk of occult nodal metastasis in sinonasal SCCs with cN0M0 tumors to support clinical decision making. METHODS: A literature search was conducted in the following three electronic databases: Medline/PubMed, ScienceDirect, and Google Scholar. Articles were assessed for eligibility in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Two independent authors extracted the data. The Methodological Items for Non-Randomized Studies (MINORS) tool was used for the assessment of biases of each included study. RESULTS: Our systematic review included six studies that met the inclusion criteria, all retrospective in design. The rate of histologically proven metastasis of sinonasal SCC to the clinically negative neck is 12.5%. Almost half of the positive cases are pathologically staged as N2 (6.5%). CONCLUSION: Our systematic review provides the rate of sinonasal SCC occult metastasis to the neck so that the surgeons can discuss with patients the risks and possible merits of adding an elective neck management in the surgical plan.

The diagnostic value of image-enhanced endoscopy system in sinonasal inverted papilloma.

PURPOSE: This study aimed to evaluate the diagnostic value of image-enhanced endoscopy (IEE) in detecting sinonasal inverted papilloma (SNIP). METHODS: Overall, 86 patients with unilateral nasal papillary or lobulated neoplasms were included between July 2018 and June 2019. All patients underwent IEE examinations, and the diagnosis of all neoplasms was confirmed through postoperative pathology. Logistic regression analysis was conducted to screen for independent predictors of various types of vascular patterns of SNIP. Furthermore, a prognostic nomogram was constructed using the independent predictors screened by logistic regression analysis to evaluate its usefulness in distinguishing SNIP from nasal polyp (NP) and papillary mucosa folds (PMF). RESULTS: In total, 86 consecutive cases were observed, including 37 with SNIP, 40 with NP, and 9 with PMF. Logistic regression analysis showed that spot, corkscrew, and multilayered vascular patterns were independent predictors of SNIP diagnosis. Furthermore, a nomogram comprising the three independent risk factors was constructed with scores of 5, 2, and 3. The area under the receiver operating characteristic curve for predicting SNIP was 0.954, 0.66, 0.71, and 0.76 for the nomogram model, spot vascular pattern, corkscrew vascular pattern, and multilayered vascular pattern, respectively. CONCLUSION: The nomogram model based on spot, corkscrew, and multilayered vascular patterns in SNIP observed using IEE can be a useful diagnostic tool for predicting and distinguishing between NP and PMF.

Choice of surgery in intestinal-type adenocarcinoma of the sinonasal tract: a long-term comparative study.

PURPOSE: Intestinal-type adenocarcinoma (ITAC) is a rare sinonasal malignancy. Curative treatment requires multidisciplinary approach, with surgical options consist of the endonasal endoscopic approach (EEA) and external surgery (EXTS). Here, we provide the post-operative and survival results from a single-center long-term follow-up. METHODS: We report long-term follow-up of 92 ITAC cases treated between 1998 and 2018, treated with EEA (n = 40) or EXTS (n = 52). Survival estimates, post-operative complications and duration of hospitalization were compared between surgical modalities. RESULTS: Baseline characteristics were similar. A higher number of T4b tumors (16%), and subsequently more tumoral invasion (39%), was present in patients undergoing EXTS compared to EEA (3% and 18%, respectively). No difference in Barnes histology subtypes was noticed. Patients undergoing EEA had a shorter post-operative hospitalization stay versus EXTS (4 versus 7 days). Use of EEA was associated to improved disease-specific survival (DSS; 11.4 versus 4.4 years; HREEA = 0.53), especially for patients with T3-4a tumors (11.4 versus 3.0 years; HREEA = 0.41). Patients with T3-4 stage, tumoral invasion, positive surgical margins, mucinous or mixed histology, and prolonged post-operative hospital stay showed poor local relapse-free, disease-free, overall, and DSS. CONCLUSIONS: Long-term follow-up in locally advanced ITAC demonstrates that resection by EEA is correlated with improved DSS compared to EXTS, especially for T3-4 tumors. No significant differences between both treatment modalities was observed regarding per- and post-operative complications, although hospitalization in patients undergoing EEA was shorter than for patients treated with EXTS. These results confirm that EEA should remain the preferred surgical procedure in operable cases of sinonasal ITAC.

Sinonasal Chondrosarcoma With Unusual Orbital Invasion.

A case is presented of a 43-year-old male with a chronic history of progressive nasal obstruction and epiphora. MRI confirmed a heterogeneous mass involving the middle and superior turbinates with T2 hyperintense and calcified components, with extension into the inferomedial orbit. Tissue biopsy revealed a grade 2 chondrosarcoma of the conventional subtype. Endonasal wide local resection of the lesion was performed with clear margins. The patient had no functional sequelae and will undergo routine surveillance.

BiZact-Assisted Endoscopic Resection of a Sinonasal Tumor.

The BiZact device, a bipolar electrosurgical scissor designed for tonsillectomy, minimizes thermal tissue damage and seals blood vessels <3 mm in diameter while dividing the soft tissue. This study describes the authors' experience with sinonasal tumor surgery using a BiZact and discusses its clinical utility and advantages. The authors analyzed BiZact-assisted endoscopic sinonasal tumor surgery cases between January 2021 and May 2023. Data were collected on patients' demographics, histopathology, extent of tumor involvement, surgical records, and postoperative medical records. Clinical utility was assessed using the success rate of complete tumor excision, estimated blood loss during surgery, device-related complications, and operation time. A survey of the surgeons' BiZact experience was also conducted. The diagnoses of the 20 patients in this study included squamous cell carcinoma (n = 2), malignant melanoma (n = 1), sarcoma (n = 1), natural killer cell lymphoma (n = 1), inverted papilloma (n = 12), angiofibroma (n = 2), and schwannoma (n = 1). This pilot study demonstrated a shortened operative time, with a median of 0.8 hours and <100 mL of intraoperative blood loss. In addition, no BiZact-related complications were observed. The BiZact device allows efficient sinonasal surgery because it has the unique advantage of one-step sealing and cutting. BiZact-assisted endoscopic sinonasal tumor surgery is a beneficial and safe procedure that reduces blood loss during surgery, shortens the operative time, and minimizes postoperative complications.

A Pilot Immunohistochemical Study Identifies Hedgehog Pathway Expression in Sinonasal Adenocarcinoma.

Tumors of the head and neck, more specifically the squamous cell carcinoma, often show upregulation of the Hedgehog signaling pathway. However, almost nothing is known about its role in the sinonasal adenocarcinoma, either in intestinal or non-intestinal subtypes. In this work, we have analyzed immunohistochemical staining of six Hedgehog pathway proteins, sonic Hedgehog (SHH), Indian Hedgehog (IHH), Patched1 (PTCH1), Gli family zinc finger 1 (GLI1), Gli family zinc finger 2 (GLI2), and Gli family zinc finger 3 (GLI3), on 21 samples of sinonasal adenocarcinoma and compared them with six colon adenocarcinoma and three salivary gland tumors, as well as with matching healthy tissue, where available. We have detected GLI2 and PTCH1 in the majority of samples and also GLI1 in a subset of samples, while GLI3 and the ligands SHH and IHH were generally not detected. PTCH1 pattern of staining shows an interesting pattern, where healthy samples are mostly positive in the stromal compartment, while the signal shifts to the tumor compartment in tumors. This, taken together with a stronger signal of GLI2 in tumors compared to non-tumor tissues, suggests that the Hedgehog pathway is indeed activated in sinonasal adenocarcinoma. As Hedgehog pathway inhibitors are being tested in combination with other therapies for head and neck squamous cell carcinoma, this could provide a therapeutic option for patients with sinonasal adenocarcinoma as well.

[ALK-positive anaplastic large cell lymphoma of paranasal sinuses: two cases report and literature review]. / ALK-pozitivnaya anaplasticheskaya krupnokletochnaya limfoma s porazheniem pridatochnykh pazukh nosa: dva klinicheskikh nablyudeniya i obzor literatury.

ALK-positive anaplastic large cell lymphoma is a rare T-cell lymphoma with ALK gene rearrangement that develops in children and young adults. The disease almost always affects the lymph nodes, and extranodal areas are also frequently involved. This article describes two cases of atypical localization of ALK-positive anaplastic large cell lymphoma with involvement of the paranasal sinuses.

High-risk human papillomavirus 16/18 associated with improved survival in sinonasal squamous cell carcinoma.

BACKGROUND: There has been conflicting evidence on the independent prognostic role of human papillomavirus (HPV) status in sinonasal cancer. The objective of this study was to assess whether the survival of patients with sinonasal cancer differs based on various HPV statuses, including HPV-negative, positive for the high-risk HPV-16 and HPV-18 (HPV16/18) subtypes, and positive for other high-risk and low-risk HPV subtypes. METHODS: In this retrospective cohort study, data from the National Cancer Database were extracted from the years 2010-2017 for patients who had primary sinonasal cancer (N = 12,009). The outcome of interest was overall survival based on HPV tumor status. RESULTS: Study included an analytic cohort of 1070 patients with sinonasal cancer who had confirmed HPV tumor status (732 [68.4%] HPV-negative; 280 [26.2%] HPV16/18-positive; 40 [3.7%] positive for other high-risk HPV; and 18 [1.7%] positive for low-risk HPV). HPV-negative patients had the lowest all-cause survival probability at 5 years postdiagnosis (0.50). After controlling for covariates, HPV16/18-positive patients had a 37% lower mortality hazard than HPV-negative patients (adjusted hazard ratio, 0.63; 95% confidence interval [CI], 0.48-0.82). Patients aged 64-72 years (crude prevalence ratio, 0.66; 95% CI, 0.51-0.86) and 73 years and older (crude prevalence ratio, 0.43; 95% CI, 0.31-0.59) presented with lower rates of HPV16/18-positive sinonasal cancer than those aged 40-54 years. In addition, Hispanic patients had a 2.36 times higher prevalence of non-HPV16/18 sinonasal cancer than non-Hispanic White patients. CONCLUSIONS: These data suggest that, for patients with sinonasal cancer, HPV16/18-positive disease may confer a significant survival advantage compared with HPV-negative disease. Other high-risk and low-risk HPV subtypes have survival rates similar to the rates for HPV-negative disease. HPV status might be an important independent prognostic factor in sinonasal cancer that could be used in patient selection and clinical decisions.

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.