Expanding the spectrum of low-grade sinonasal adenocarcinoma with biphasic seromucinous differentiation and activating HRAS/AKT1 mutations.

AIMS: Low-grade non-intestinal-type sinonasal adenocarcinoma (LGSNAC) is a rare heterogeneous and poorly characterised group of tumours, distinct from intestinal- and salivary-type neoplasms. Therefore, further characterisation is needed for clearer biological understanding and classification. METHODS AND RESULTS: Clinical, histological and molecular characterisation of four cases of biphasic, low-grade adenocarcinomas of the sinonasal tract was performed. All patients were male, aged between 48 and 78 years, who presented with polypoid masses in the nasal cavity. Microscopically, virtually all tumours were dominated by tubulo-glandular biphasic patterns, microcystic, focal (micro)papillary, oncocytic or basaloid features. Immunohistochemical staining confirmed biphasic differentiation with an outer layer of myoepithelial cells. Molecular profiling revealed HRAS (p.G13R, p.Q61R) mutations, and concomitant AKT1 (p.E17K, p.Q79R) mutations in two cases. Two cases showed potential in-situ/precursor lesions adjacent to the tumour. Follow-up periods ranged from 1 to 30 months, with one case relapsing locally after 12 and > 20 years. CONCLUSION: This study further corroborates a distinct biphasic low-grade neoplasm of the sinonasal tract with seromucinous differentiation. Although morphological and molecular features overlap with salivary gland epithelial-myoepithelial carcinoma, several arguments favour categorising these tumours within the spectrum of LGSNAC.

Sinonasal mucosal melanoma treatment response assessment to immune checkpoint inhibitors using hybrid positron emission tomography imaging.

The purpose of this retrospective study was to investigate response of sinonasal mucosal melanoma (SMM) patients to treatment with immune checkpoint inhibitors (ICI), using hybrid PET imaging. Fifteen SMM patients underwent hybrid PET imaging before and three months after initiation of ICI. The disease-specific survival (DSS) was calculated. Quantitative PET parameters of the primary tumor and their association with DSS and therapy response were investigated. Nine of the fifteen (60%) patients responded to ICI therapy. Patients with therapy response depicted on hybrid PET imaging had better DSS than those without (p = 0.0058). Quantitative PET parameters of the initial PET harbored no association with DSS or therapy response. However, these findings lack of sufficient statistical power and must be interpreted with caution. The first restaging PET-imaging after ICI initiation can help stratify patients with regard to DSS.

Rhinologic outcome of endoscopic transnasal-transsphenoidal pituitary surgery: an institutional series, systematic review, and meta-analysis.

PURPOSE: We aimed to summarize the available data on the objective rhinologic outcome after endoscopic transnasal-transsphenoidal (ETT) surgery. METHODS: Retrospective study on a consecutive cohort of treatment-naïve patients undergoing ETT pituitary gland surgery. Additionally, a systematic review and meta-analysis with focus on the rhinologic outcome, including postoperative smell function was performed. RESULTS: The institutional series incorporated 168 patients. A concomitant endoscopic septoplasty was performed in 29/168 patients (17.3%). A nasoseptal flap was used for reconstruction of large skull-base defects or high-flow CSF leaks in 4/168 (2.4%) patients. Early postoperative rhinologic complications (< 4 weeks) included epistaxis (3%), acute rhinosinusitis (1.2%) and late postoperative complications (≥ 8 weeks) comprised prolonged crusting (15.6%), symptomatic synechiae (11.9%) and septal perforation (0.6%). Postoperative smell function was not impaired (Fisher's exact test, p = 1.0). The systematic review included 19 studies on 1533 patients with a median postoperative epistaxis rate of 1.4% (IQR 1.0-2.2), a postoperative acute rhinosinusitis rate of 2.3% (IQR 2.1-3.0), a postoperative synechiae rate of 7.5% (IQR 1.8-19.1) and a postoperative septal perforation rate of 2.2% (IQR 0.5-5.4). Seven studies including a total of 206 patients reported adequate outcome measures for smell function before and after ETT surgery. Only 2/7 studies reported an impairment of smell function postoperatively, especially in patients with nasoseptal flap harvesting. CONCLUSION: Early and late postoperative rhinologic complication rates after ETT surgery for pituitary lesions seem to be low. A thorough evaluation of smell function, in particular in patients at risk for nasoseptal flap harvesting, may be an important factor in optimal postoperative care.

Ex vivo and in vivo evaluation of transsphenoidal Liqoseal application to prevent cerebrospinal fluid leakage.

BACKGROUND: Despite improvements in closure techniques by using a vital nasoseptal flap, the use of sealing materials, and improved neurosurgical techniques, cerebrospinal fluid (CSF) leak after transsphenoidal surgery still is a clinically relevant problem. Liqoseal® (Polyganics bv, Groningen, The Netherlands) is a CE-approved bioresorbable sealant patch for use as an adjunct to standard methods of cranial dural closure to prevent CSF leakage. This study aims to evaluate the application of Liqoseal in transsphenoidal surgery ex vivo and in vivo. METHODS: 1. We created an ex vivo setup simulating the sphenoidal anatomy, using a fluid pump and porcine dura positioned on a conus with the anatomical dimensions of the sella to evaluate whether the burst pressure of Liqoseal applied to a bulging surface was above physiological intracranial pressure. Burst pressure was measured with a probe connected to dedicated computer software. Because of the challenging transsphenoidal environment, we tested in 4 groups with varying compression weight and time for the application of Liqoseal. 2. We subsequently describe the application of Liqoseal® in 3 patients during transsphenoidal procedures with intraoperative CSF leakage to prevent postoperative CSF leakage. RESULTS: 1. Ex vivo: The overall mean burst pressure in the transsphenoidal setup was 231 (± 103) mmHg. There was no significant difference in mean burst pressure between groups based on application weight and time (p = 0.227). 2. In Vivo: None of the patients had a postoperative CSF leak. No nose passage problems were observed. One patient had a postoperative meningitis and ventriculitis, most likely related to preoperative extensive CSF leakage. Postoperative imaging did not show any local infection, swelling, or other device-related adverse effects. CONCLUSIONS: We assess the use of Liqoseal® to seal a dural defect during an endoscopic transsphenoidal procedure as to be likely safe and potentially effective.

Combinational expression of tumor testis antigens NY-ESO-1, MAGE-A3, and MAGE-A4 predicts response to immunotherapy in mucosal melanoma patients.

PURPOSE: Immunotherapy using immune checkpoint inhibitors (ICI) has revolutionized cancer treatment in recent years, particularly in melanoma. While response to immunotherapy is associated with high tumor mutational burden (TMB), PD-L1 expression, and microsatellite instability in several cancers, tumors lacking these biomarkers can still respond to this treatment. Especially, mucosal melanoma, commonly exhibiting low TMB compared to cutaneous melanoma, may respond to immunotherapy with immune checkpoint inhibitors. Therefore, the aim of our study was to investigate novel biomarkers in mucosal melanoma that predict response to combined ipilimumab and nivolumab. METHODS: We investigated 10 tumor samples from 10 patients (three responders, seven non-responders) before treatment and six tumor samples from five patients after progression using a targeted Next Generation Sequencing (NGS) gene expression panel. The findings were corroborated with an independent method (i.e., immunohistochemical staining) on the same 10 tumor samples before treatment and, to increase the cohort, in addition on three tumor samples before treatment of more recent patients (one responder, two non-responders). RESULTS: With the targeted gene expression panel, we found the three tumor testis antigens CTAG1B (NY-ESO-1), MAGE-A3, and MAGE-A4 to be predominantly expressed in responding tumors. This marker panel was either not or not completely expressed in non-responders (p < 0.01). Using immunohistochemistry for all three markers, we could confirm the elevated expression in tumors responding to the ipilimumab/nivolumab combination therapy. CONCLUSION: In conclusion, these three biomarkers await validation in a larger patient cohort and could be easily used in future routine diagnostics to predict the outcome of ipilimumab/nivolumab combination therapy in mucosal melanoma patients.

Reappraisal of Grading in Intestinal-Type Sinonasal Adenocarcinoma: Tumor Budding as an Independent Prognostic Parameter.

Since sinonasal intestinal-type adenocarcinomas (ITAC) show resemblance to colorectal adenocarcinomas, we aimed to investigate novel prognostic factors of outcome, with particular focus on the role of tumor budding (TB). Retrospective clinico-pathological single-institution study on consecutive ITAC patients between 1996 and 2020. Histopathological parameters including conventional subtypes and TB features (low, intermediate, high) were evaluated with the aid of pancytokeratin (AE1/AE3) immunohistochemical staining. Parameters were correlated to clinical data and outcome. A total of 31 ITAC patients were included. Overall, 19/31 patients (61.3%) presented with stage III/IV disease. Presence of lymph node or distant metastases was rare (1/31 patient, 3.2%). Treatment protocols consisted of tumor resection in 30/31 patients (96.8%) and primary radiochemotherapy in 1/31 patient (3.2%). Adjuvant radiation therapy was conducted in 20/30 surgically treated patients (66.7%). The 3- and 5-year overall survival (OS) was 83.9% and 78.3% and the 3- and 5-years disease-specific survival (DSS) 83.7% % and 78.5%, respectively. The presence of intermediate/high TB (defined as ≥ 5 buds) was associated with both, worse DSS (log rank p = 0.03) and OS (log rank p = 0.006). No patient with low TB revealed progressive disease or died of the disease. No association between TB and tumor stage or conventional tumor subtype was found. Tumor budding seems to be an independent prognostic factor of worse outcome in ITAC.

The Role of Regional Disease and Patterns of Treatment Failure in Primary Sinonasal Malignancies.

BACKGROUND: The question how to treat the clinically negative neck in sinonasal malignancies is controversial. OBJECTIVES: To investigate patterns of treatment failure and to assess outcome measures in patients with primary sinonasal malignancies. METHODS: Retrospective cohort study of patients treated for primary malignant sinonasal malignancies. RESULTS: Lymph node (LN) metastases at initial presentation were present in 8 of 152 patients (5.3%). Ipsi- and contralateral LN levels 1 and 2 were identified as nodal basins at risk. We found a 5-year overall survival (OS) of 75.2% and disease free survival of 61.1%. Among patients with cN0 neck, nodal recurrence free survival was not different between patients with and without elective neck treatment (P = .23). On logistic regression analysis, we found initial T classification as an independent factor for achievement of complete remission (CR) and OS. CONCLUSIONS: LN metastases at initial presentation are rare and initial T classification was identified as the most important prognostic factor for OS and CR, emphasizing the need for a thorough initial staging of the primary tumor.

Diagnostic pathway and stage migration of sinonasal malignancies in the era of the COVID-19 pandemic.

OBJECTIVES: The COVID-19 pandemic bears the risk of delayed cancer diagnoses. METHODS: Study on the diagnostic pathway of sinonasal malignancies during the COVID-19 pandemic. RESULTS: Median time from first symptom to treatment initiation was not increased during the pandemic: 137 days (interquartile range [IQR] 104-193) vs 139 days (IQR 103-219) (P = .60). Median time from first appointment at our institution to treatment initiation was even reduced in 2020: 18 days (IQR 11-25) vs 11 days (IQR 7-17) (P = .02). A trend toward advanced tumor stages during the pandemic was seen: 11/30 patients (36.7%) ≥ stage 4 in 2018 to 2019 vs 12/19 patients (63.2%) ≥ stage 4 in 2020 (P = .064). CONCLUSION: Both, time to diagnosis and time to treatment initiation were similar during the pandemic. However, a higher proportion of advanced tumors stages was observed. Despite the pandemic, we provided a swift diagnostic workflow, including a virtual tumor board decision and a prompt treatment initiation. Level of Evidence: 4.

Reduction of otorhinolaryngological consultations due to the COVID-19 lockdown and its impact on disease progression.

OBJECTIVES: To compare consultations at the Otorhinolaryngological Department at a tertiary referral centre between the COVID-19 lockdown in 2020 and the same period in 2019, as well as to study the impact of deferring visits on disease progression. METHODS: The emergency consultations during these time periods were analysed retrospectively. The effect of postponing appointments on disease progression was examined for 122 patients with chronic rhinosinusitis, for 50 patients with a benign tumour and for 22 patients with the diagnosis of a malignant tumour. To compare disease progression, patients with the diagnosis of a malignant tumour were matched to patients seen over the same period in 2019. RESULTS: During the lockdown, a reduction of 44.1% in emergency consultations compared with 2019 was observed. The largest significant decrease of consultation numbers was seen for otitis media and for Eustachian tube dysfunction. Fewer patients with tonsillitis sought emergency assistance; however, no difference in frequency of abscesses was observed. Disease progression was seen in 44.4% of patients with chronic rhinosinusitis. In 2020, 18.8% of patients with the diagnosis of a malignant tumour showed disease progression, yet no difference from the previous year was observed. CONCLUSION: Fewer emergency consultations took place during the COVID-19 lockdown; among others, there were fewer visits due to otitis media and tonsillitis. However, no change in the incidence of complications was noted. Almost 50% of patients with chronic rhinosinusitis showed disease progression, leading to prolonged suffering due to the rescheduling of appointments. The treatment of patients with the diagnosis of a malignant tumour was not affected by the postponement of consultations.

Whole-body hybrid positron emission tomography imaging yields clinically relevant information in the staging and restaging of sinonasal tumors.

BACKGROUND: Whole-body hybrid positron emission tomography (PET) imaging is increasingly used for sinonasal tumors. However, only empirical data exist on the additional, clinically relevant information derived from these techniques. METHODS: This study included 96 regionalized magnetic resonance imaging (MRI) of the sinonasal tract/neck and separate hybrid FDG-PET/CT or FDG-PET/MRI in 74 patients. Additional radiological information (ARI) obtained from each hybrid examination was analyzed and its clinically relevance was determined. Clinically relevant information (CRI) was categorized with regard to primary tumor site, regional lymph node metastases, distant metastases, second primary tumors, and non-neoplastic findings. RESULTS: A total of 45/96 (46.9%) hybrid PET examinations revealed ARI. CRI was found in 32/96 (33.3%) examinations and concerned the primary tumor site (6.1%), regional lymph node metastases (4.1%), distant metastases (14.3%), second primary tumors (7.3%), and non-neoplastic findings (5.1%). CONCLUSIONS: Hybrid PET imaging yields additional radiological information translating into clinically relevant information in a substantial proportion of patients with sinonasal tumors.

Who's Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma.

Mucosal melanoma can be driven by various driver mutations in genes such as NRAS, KIT, or KRAS. However, some cases present with only weak drivers, or lacking known oncogenic drivers, suggesting immunotherapy over targeted therapy. While resistance mechanisms to immunotherapy in cutaneous melanoma have been uncovered, including alterations in JAK1/2, B2M, or STK11, a switch of oncogenic drivers under immunotherapy has not yet been observed. We report three cases of metastatic sinonasal melanoma that switched oncogenic drivers from KRAS, KIT, or no driver to NRAS during or after immunotherapy, thereby showing progressive disease. One of the cases presented with three spatially separate driver mutations in the primary tumor, whereas the NRAS clone persisted under immunotherapy. In comparison, three different control cases receiving radiotherapy only did not show a change of the detectable molecular drivers in their respective recurrences or metastases. In summary, these data provide an important rationale for longitudinal molecular testing, based on evidence for an unforeseen recurrent event of molecular driver switch to NRAS in progressing sinonasal melanoma. These findings provide the basis for further studies on a potential causal relation of emerging NRAS mutant clones and immunotherapy.

Assessment of Surgical Complications With Respect to the Surgical Indication: Proposal for a Novel Index.

Introduction: The Clavien-Dindo classification is a broadly accepted surgical complications classification system, grading complications by the extent of therapy necessary to resolve them. A drawback of the method is that it does not consider why the patient was operated on primarily. Methods: We designed a novel index based on Clavien-Dindo but with respect to the surgical indication. We surveyed an international panel of otolaryngologists who filled out a questionnaire with 32 real case-inspired scenarios. Each case was graded for the surgical complication, surgical indication, and a subjective rating whether the complication was acceptable or not. Results: Seventy-seven otolaryngologists responded to the survey. Mean subjective rating and surgical complication grading for each scenario showed an inverse correlation (r 2 = 0.147, p = 0.044). When grading the surgical complication with respect to the surgical indication, the correlation with the subjective rating increased dramatically (r 2 = 0.307, p = 0.0022). Conclusion: We describe a novel index grading surgical complications with respect to the surgical indication. In our survey, most respondents judged a complication as acceptable or not according to its grade but kept in mind the surgical indication. This subjective judgment could be quantified with our novel index.

Hybrid positron emission tomography imaging for initial staging of sinonasal tumors: Total lesion glycolysis as prognosticator of treatment response.

BACKGROUND: To assess hybrid positron emission tomography (PET) imaging in the initial staging and outcome prediction of sinonasal malignancies. METHODS: Retrospective study on patients with sinonasal malignancies undergoing hybrid PET imaging for initial staging. RESULTS: Complete remission (CR) was achieved in 45 of 65 patients (69.2%). Overall sensitivity for detection of primaries using 18F-fluoro-deoxy-d-glucose PET (FDG-PET) was 95.4%, for lymph node metastases 100% and distant metastases (DM) 100%. On univariate analysis, PET parameter total lesion glycolysis (TLG) was associated with achieving CR after primary treatment (176.8 ± 157.2 vs 83.7 ± 110.8, P = .03). Multivariate logistic regression demonstrated that TLG adjusted for the T classification best predicted achievement of CR. CONCLUSIONS: Hybrid PET imaging yields an excellent sensitivity in detecting primary tumors, lymph node metastases and DM in sinonasal malignancies. TLG of the primary tumor is an independent prognostic factor for achieving CR after initial treatment.

Surgery as Single-Modality Treatment for Early-Stage Olfactory Neuroblastoma: An Institutional Experience, Systematic Review and Meta-analysis.

BACKGROUND: For olfactory neuroblastoma (ONB), the combination of surgical tumor resection and radiation therapy (RT) has been considered the "gold standard" in treatment protocols intended to cure. OBJECTIVE: To summarize evidence on the treatment of ONB using surgery alone. METHODS: A retrospective institutional case series, a systematic review of the literature, and an individual patient data (IPD) meta-analysis on only surgically treated ONB patients. RESULTS: At our institution, a total of 10 patients were treated through surgery alone and remained alive and free of disease at last follow-up. The IPD meta-analysis on 128 patients revealed a disease-free survival (DFS) and overall survival (OS) of 67.7% and 75.4% at 5 years and 57.1% and 71.9% at 10 years, respectively. Univariate analysis showed that Kadish stage C/D and Hyams grading III//IV significantly affected OS (P = 0.000 and P = 0.000) and DFS (P = 0.000 and P = 0.002). For low-risk patients, the DFS was 80.6% at 5 years and 67.8% at 10 years, respectively. CONCLUSIONS: Surgery alone is an equivalent alternative to combined treatment in carefully selected low-risk ONB patients with better outcome measures than previously reported.

Need for long-term follow-up in sinonasal inverted papilloma: A Single-institution experience.

BACKGROUND: Most studies on sinonasal inverted papillomas (SNIPs) regarding risk factors for recurrence, recurrence rates (RRs) and malignant transformation are biased by a significant proportion of revision cases. METHODS: Retrospective study on patients with consecutive, treatment-naïve SNIPs at a tertiary referral center between 1999 and 2019. RESULTS: Overall, RR was 9.8% (10 of 102 patients), with 2 of 10 recurrences (20%) occurring after more than 5 years. Histopathological workup revealed synchronous malignancy in 2 of 102 patients (2%). Subgroup analysis revealed a significantly higher RR for SNIPs involving the frontal sinus (26.3% vs 6.0%, P = .02). No SNIPs primarily originating from the frontal sinus were observed. CONCLUSION: Overall, RR of treatment-naïve SNIPs is comparably low; however, long-term follow-up is mandatory due to late recurrences. Secondary involvement of the frontal sinus was identified as risk factor for recurrence. No SNIPs primarily originating from frontal sinus were observed.

Assessing the surgical outcome of the "chopsticks" technique in endoscopic transsphenoidal adenoma surgery.

OBJECTIVE: The "chopsticks" technique is a 3-instrument, 2-hand mononostril technique that has been recently introduced in endoscopic neurosurgery. It allows a dynamic surgical view controlled by one surgeon only while keeping bimanual dissection. Being a mononostril approach, it requires manipulation of the mucosa of one nasal cavity only. The rationale of the technique is to reduce nasal morbidity without compromising surgical results and complication rates. There are, however, no data available on its results in endoscopic surgery (transsphenoidal surgery [TSS]) for pituitary adenoma. METHODS: The authors performed a cohort analysis of prospectively collected data on 144 patients (156 operations) undergoing TSS using the chopsticks technique with 3T intraoperative MRI. All patients had at least 3 months of postoperative neurosurgical, endocrinological, and rhinological follow-up (Sino-Nasal Outcome Test-20 [SNOT-20] and Sniffin' Sticks). The surgical technique is described, and the achieved gross-total resection (GTR) and extent of resection (EOR) together with patients' clinical outcomes and complications are descriptively reported. RESULTS: On 3-month postoperative MRI, GTR was achieved in 71.2% of patients with a mean EOR of 96.7%. GTR was the surgical goal in 122 of 156 cases and was achieved in 106 of 122 (86.9%), with a mean EOR of 98.7% (median 100%, range 49%-100%). There was no surgical mortality. At a median follow-up of 15 months (range 3-70 months), there was 1 permanent neurological deficit. As of the last available follow-up, 11.5% of patients had a new pituitary single-axis deficit, whereas 26.3% had improvement in endocrinological function. Three patients had new postoperative hyposmia. One patient had severe impairment of sinonasal function (SNOT-20 score > 40). The operation resulted in endocrine remission in 81.1% of patients with secreting adenomas. CONCLUSIONS: This study shows that the chopsticks technique confers resection and morbidity results that compare favorably with literature reports of TSS. This technique permits a single surgeon to perform effective endoscopic bimanual dissection through a single nostril, reducing manipulation of healthy tissue and thereby possibly minimizing surgical morbidity.

Diagnostic accuracy of computed tomography and magnetic resonance imaging compared to surgical exploration for anterior skull base and medial orbital wall infiltration in advanced sinonasal tumors.

BACKGROUND: Knowledge of medial orbital wall (MOW) and anterior skull base (ASB) infiltration is of uttermost importance for staging and therapy planning of advanced sinonasal tumors. METHODS: We assessed the diagnostic performance of preoperative computed tomography (CT) and magnetic resonance imaging (MRI) for MOW and ASB infiltration compared to intraoperative exploration. RESULTS: Both CT and MRI yielded higher diagnostic accuracy for MOW infiltration (Reader 1: 83.6% CT; 89.0% MRI, Reader 2: 91.8% CT, 93.2% MRI) than for ASB infiltration (Reader 1: 82.2% CT, 82.2% MRI, Reader 2: 67.7% CT, 67.7% MRI). Both modalities were equal to the gold standard, except for ASB assessment by Reader 2 with MRI. A postoperative change of T classification is common (Reader 1: 28.8%, Reader 2: 31.5%). CONCLUSIONS: CT and MRI are accurate methods for the assessment of MOW infiltration. ASB assessment is challenging and false-positive and false-negative findings are common with both methods, emphasizing the need for intraoperative exploration.

Progressive Disease in Sentinel-negative Melanoma Patients: Biological Differences and Importance of Sentinel Lymph Node Biopsy.

BACKGROUND/AIM: Among the most important prognostic factors in melanoma is the sentinel lymph node (SLN) status. MATERIALS AND METHODS: Using our electronic database we identified 109 of 890 SLN-negative patients with progressive disease (PD). These patients were characterized for melanoma type, molecular type, sequence and extent of metastatic spread. RESULTS: A total of 61 of 109 SLN-negative patients had PD in the SLN-basin indicating false-negative SLN (group-1). Forty eight of 109 patients had PD at distant sites and were therefore impossible to be identified using SLN biopsy (group-2). Despite distant spread these patients had significantly more single organ metastasis (p<0.001) and significantly longer disease-free-survival (p=0.001) compared to group-1. Additionally, to significant differences on a molecular basis between the two groups (p=0.01), all lentigo maligna and spindle-cell-melanomas belonged to group-2 and all, except one lentigo maligna melanoma, had single visceral metastasis. CONCLUSION: Two different biological groups among SLN-negative patients with PD were demonstrated. Extravascular-migratory-metastasis, rather than hematogenous spread, might be responsible for the observed PD with single organ involvement.

HPV-Related Multiphenotypic Sinonasal Carcinoma: Four Cases that Expand the Morpho-Molecular Spectrum and Include Occupational Data.

HPV-related multiphenotypic sinonasal carcinoma (HMSC) is a recently described distinct tumor entity of the sinonasal tract associated with high-risk subtypes of human papilloma virus (HPV), predominantly type 33. The biological behavior seems to be less aggressive than the often high-grade, highly proliferative morphology implies; however, recurrences are frequent. Most of the cases present as polypoid tumors within the nasal cavity. Microscopic morphology frequently encompasses adenoid cystic-like features or features reminiscent of other salivary gland tumors. Here, we describe four cases of this rare entity, all observed in women. The polypoid tumors were within the nasal cavity, leading to obstruction, facial pain and epistaxis. The morphology was predominantly basaloid, solid and adenoid cystic-like in two of four cases, one with additional glomeruloid features. Another case showed basaloid tumor cells with prominent mature squamous differentiation and extensive keratinization. A single case showed a predominantly solid and reticular growth pattern. All cases were diffusely positive for p16 (100%), expressed SOX10, LEF-1 and partially S-100, and harbored HPV high-risk types 33, 56 (2×) and 82. No recurrences or metastases were detectable after 3-50 months of follow-up. Of note, three of four patients were nurses/nursing assistant. We expand the morphological spectrum by describing a glomeruloid growth pattern and extensive mature keratinization, and add HPV type 82 to the molecular spectrum. The finding of HMSC among predominantly nurses in our cohort warrants further epidemiological studies in larger cohorts.