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PURPOSE: DEK::AFF2 fusion-associated squamous cell carcinoma (DEK::AFF2 SCC), also reported in the literature as low-grade papillary sinonasal (Schneiderian) carcinoma (LGPSC), is a rare, primarily bland-appearing, but locally aggressive neoplasm. Morphologically, these tumors can closely resemble sinonasal papilloma (SP), especially on small or limited biopsy, often leading to misdiagnosis. DEK::AFF2 SCC is devoid of the underlying mutually exclusive EGFR or KRAS driver mutations of SP, suggesting it may represent a distinct unique entity. METHODS: In this study, we conducted a retrospective search of "unusual" SP reported either as atypical, dysplastic, or suspicious for malignant transformation at our institution in the last 13 years (2010-2023), to identify potential cases of DEK::AFF2 SCC. RESULTS: Of the 201 SP cases during this time period, 30 "unusual" SP cases were identified. On morphologic review of these 30 cases, 6 were worrisome for DEK::AFF2 SCC and were selected for AFF2 immunohistochemical stain (IHC), of which 3 cases were positive. All 3 AFF2 IHC positive cases were also positive for DEK::AFF2 fusion by fluorescence in situ hybridization (FISH), thereby, confirming IHC results. CONCLUSIONS: This study highlights that AFF2 IHC can be an invaluable surrogate marker to FISH in identifying DEK::AFF2 SCC in challenging cases to avoid misdiagnosis. Detailed clinical and pathologic data were collected to gain a better understanding of this emerging challenging entity. A literature review was performed to enrich our knowledge of DEK::AFF2 SCC.

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OBJECTIVES: Exophytic Sinonasal Papilloma (ESP) is a benign tumor of the sinonasal tract. Complete surgical excision by endoscopic surgery is the treatment of choice. However, a high recurrence rate (36% at 5-year follow-up) is associated with this method, which may indicate the presence of microorganisms such as Human Papillomavirus (HPV). It is important to note that the standard treatment for ESP does not include antiviral drugs. In our study, we are testing the effectiveness of an interferon-containing drug in reducing recurrence and postoperative reactions in patients with ESP. METHODS: We included 78 patients aged 23-83 years with a confirmed diagnosis of ESP by rhinoscopy and nasal endoscopy and a positive PCR test for HPV in nasal scrapings. To compare the results, we divided the patients into main and control groups. The main group received recombinant human interferon after surgery, while the control group did not receive the drug. We performed a statistical analysis to compare the proportion of patients without reactive manifestations at different stages of the postoperative period, as well as to compare the proportion of patients with recurrent ESP at certain stages of observation. RESULTS: The introduction of recombinant human interferon accelerated the resolution of postoperative reactions and promoted the healing of the nasal mucosa after surgical removal of the ESP. We also found a statistically significant association between treatment with recombinant interferon and a reduction in the recurrence rate of ESP. CONCLUSION: According to the results of the study, it was found that in the main group of patients who received rhIFN-α2b (recombinant human Interferon alpha 2b) in the postoperative period, the frequency of relapses of ESP and the time of postoperative recovery were significantly lower than in patients in the control group who did not take the drug. LEVEL OF EVIDENCE: Cohort Study.

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We communicate here two complete Human papillomavirus 11 (HPV11) genomes recovered from one transitional and from one squamous inverted sinonasal papilloma, a rare proliferative disease in humans. Both genomes belong to the HPV11_A2 sublineage.

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Objectives: To evaluate the clinical and prognostic behaviors of sinonasal papillomas. Methods: Patients diagnosed with sinonasal papilloma were reviewed between 2001 and 2016 at a tertiary rhinology practice. Using pathology-specific electronic medical record software, patients diagnosed with sinonasal papilloma were identified. Four subcategories of this lesion were identified: inverting (IP), exophytic (EP) oncocytic (OP) and inverting + exophytic (IP + EP) papillomas. Results: A total of 107 patients were identified with unique sinonasal papilloma diagnoses. Of these, the majority were diagnosed with IP (87, 81.3%). The subpopulation of patients co-diagnosed with IP and EP (IP + EP) was unique with respect to clinical presentation and prognosis relative to both the IP and EP alone populations. IP + EP patients (5, 4.7%) were older with an average age of 75.25 years compared to 45 (EP) and 55.26 (IP), p < .0001. IP + EP patients more often presented with epistaxis (60%) compared to 33.3% (EP) and 4.6% (IP). Finally, all IP + EP patients had at least one recurrence of their disease, compared to 33.3% (EP) and 28.5% (IP). Conclusions: Each histopathologic subtype of sinonasal papilloma has unique clinical characteristics and recurrence rates after surgical resection. The subpopulation of patients diagnosed with IP + EP tends to be older, more likely to present with epistaxis, and more likely to recur. Additional investigation and analysis of this subpopulation is warranted. Level of Evidence: 4.

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BACKGROUND: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field. METHODS: In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication. RESULTS: The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. CONCLUSION: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses.

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Carcinomas of the head-and-neck region with squamous and glandular/mucinous features constitute a heterogeneous group, with a significant minority of tumors showing an human papillomavirus (HPV) association. The differential diagnosis is usually between mucoepidermoid carcinoma (MEC) and adenosquamous carcinoma. We present here two tumors that exemplify both the challenges of diagnostic classification, as well as the complex relationship to HPV: (a) a low risk HPV positive/p16 negative carcinoma that is most consistent with a relatively typical intermediate grade mucoepidermoid type carcinoma with complete MEC phenotype (three cell types), originating from intranasal sinonasal papillomas with exophytic and inverted patterns, and invading surrounding maxillary compartments, and (b) a p16 and keratin 7 (KRT7) positive carcinoma of the right tonsil, characterized by stratified squamous and mucinous cell (mucocyte) features. Whereas the first tumor represents a typical MEC ex-Schneiderian papilloma, the second is morphologically most consistent with the, novel for this anatomic location, diagnosis of "invasive stratified mucin producing carcinoma" (ISMC), pointing to an analogy to similar, high-risk HPV-driven malignancies recently described in the gynecologic (GYN) and genitourinary (GU) areas. Both tumors, despite their mucoepidermoid-like features had no connection to salivary glands and lacked the MAML2 translocation typical of salivary gland MEC, pointing to a mucosal/non-salivary gland origin. Using these two carcinomas as examples, we attempt to address questions related to: (a) the histological distinction between MEC, adenosquamous carcinoma, and ISMC, (b) similarities and differences between these histological entities in mucosal sites versus morphologically similar salivary gland tumors, and (c) the role of HPV in these tumors.

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Inverted sinonasal papillomas, also referred to as Schneiderian papillomas, are benign tumors originating from the Schneiderian membrane that lines the nasal cavity and paranasal sinuses. They frequently display an endophytic growth pattern, in which the stroma beneath is invaded by epithelial cells. The exact cause of inverted sinonasal papillomas is unknown, but several theories have been offered. The most widely accepted theory states that these tumours arise from the metaplasia of the respiratory epithelium into a stratified squamous epithelium. This metaplastic process is thought to be brought on by irritant exposure, chronic inflammation, or viral infections like the human papillomavirus (HPV). While inverted sinonasal papillomas commonly arise from the paranasal sinuses and lateral walls of the nasal cavity, their occurrence from the nasal septum is relatively rare. Additionally, although inverted sinonasal papillomas are typically benign, they can exhibit locally aggressive behaviour and damage nearby structures. The histopathological examination revealed nuclear atypia, which raises questions about the potential for malignant transformation. We describe a rare case of an inverted sinonasal papilloma that developed from the nasal septum. The tumour spread into the septum's anterior cartilaginous region, causing the cartilage to deteriorate and develop mucosal defects. The rarity of an inverted sinonasal papilloma arising from the nasal septum along with its impact on cartilaginous septum is discussed. Careful monitoring and prolonged follow-up are therefore necessary to spot any signs of recurrence or malignant changes.

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Introduction and importance: Sinonasal inverted papilloma is a rare benign tumor of the nasal cavity and paranasal sinuses (PNS). Radiological evaluation is the key to management. Case presentation: A 46-year-old male presented with complaints of right nasal congestion and occasional bleeding for 4 months. During anterior rhinoscopy, a pinkish fleshy mass occupying the right nasal cavity was seen. X-ray and computed tomography (CT) PNS view showed opacification in the right nasal cavity and maxillary sinus. An MRI of the nose and PNS revealed a peculiar convoluted striated/cerebriform pattern. Histopathology report described the features of an inverted papilloma. The patient underwent endoscopic removal of the mass under general anesthesia. Surgical resection of the tumor was performed along with adjacent normal mucosal tissues. The patient recovered well and was followed-up for recurrence. Clinical discussion: Sinonasal inverted papilloma is commonly found in males in their fifth to sixth decade of life. A CT scan is the initial modality of choice to evaluate the extent of the disease. MRI is superior to CT in distinguishing tumors from other conditions as well as to evaluate soft tissue extensions. Involvement of the frontal sinus is a risk factor for recurrence. The first option for treating an inverted papilloma is complete surgical removal with the adjacent uninvolved mucosa. Conclusion: In a biopsy-proven case, radiological assessments like CT and MRI play a pivotal role in studying the typical morphology, delineating the extension, and detecting recurrence.

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Various malignant and benign tumors can arise in the sinonasal cavity, including inverted papilloma (IP), a benign neoplasm with unique clinical characteristics. However, the mechanisms involved in the recurrence, occurrence, and malignant transformation of IP remain debatable. This study aimed to investigate the impact of human papillomavirus (HPV) infections on IP by comparing the number of infections in cases with epithelial tissue dysplasia and explore the predictive role of proliferative and prognostic markers in dysplasia. Tissue blocks from 35 cases of sinonasal papilloma, collected between 2015 and 2021 from the laboratory archives of the Medical City of Ghazi Al-Hererri Hospital in Baghdad, Iraq, were immunohistochemically stained with monoclonal antibodies (mAbs) to detect Ki-67 and p53. A quantitative immunohistochemical analysis was conducted to analyze the results. Polymerase chain reaction (PCR) was performed to detect HPV genotypes 16/18 and 6/11 in the tissues. There was an insignificant increase in Ki-67 and p53 expression in inverted papillomas with dysplasia. HPV11 was the most prevalent genotype in 34.3% of the patients, followed by HPV16 and HPV18 in 31.4% of the patients for each virus. The least common virus detected was human papillomavirus 6 (8.6%), which did not show any significant association with the degree of dysplasia. Viral detection proliferation and apoptosis had no impact on tumor dysplasia amongst all the patients, showing no relationship with the evaluated cases.

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The sinonasal tract is considered a second hotspot for human papillomavirus (HPV)-related tumors in the head and neck, with HPV being identified in up to 62% of squamous cell carcinomas (SCCs) and 38% of papillomas. There is limited data from geographical regions with low prevalence of high-risk (HR)-HPV on the association of HR-HPV in sinonasal neoplasms and on utility of p16 as a surrogate marker. p16 immunohistochemistry, HR-HPV mRNA ISH and quantitative real-time PCR (qPCR) were performed on a retrospective cohort of sinonasal papillomas and SCCs. KRAS mutation analysis was done in oncocytic papillomas. p16 positivity was present in 22/142 cases (15.5%) including eight inverted papillomas, one oncocytic papilloma (OP), and 13 SCC. Among these, mRNA ISH showed HR-HPV in the OP and two SCC, while another SCC was found to harbour HPV18 by qPCR. Two HPV-associated SCCs had foci of OP. mRNA ISH was negative in all p16 negative cases. p16 immunohistochemistry showed 68% concordance with mRNA ISH, and had sensitivity and negative predictive value of 100%; specificity was 67%, and positive predictive value was 14.3%. Association with HR-HPV in sinonasal papillomas and SCC is rare, and may be seen in cases demonstrating oncocytic morphology. p16 immunohistochemistry has low specificity and positive predictive value in low-prevalence populations; thus, reflex direct HR-HPV testing should be performed in p16 immunopositive cases. This two-step approach is viable in resource-limited settings, as the proportion of p16 positive cases is small.

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Sinonasal biopsy specimens are a challenging area in anatomic pathology. The small, often fragmented or crushed nature of these biopsies can hinder morphologic assessment. Additionally, many of the tumors in this area are rare and share morphologic, and sometime immunophenotypic similarities. In many cases, immunohistochemistry is helpful if not necessary to reach a specific diagnosis. In other cases, a specific diagnosis is not possible and a differential diagnosis must be given on a biopsy specimen despite access to a well-equipped immunohistochemistry laboratory. This review article groups some of the more challenging entities in the sinonasal region based on morphologic patterns. These include low grade squamoid lesions such as sinonasal (Schneiderian) papilloma and DEK::AFF2 rearranged carcinoma, glandular neoplasms such as intestinal and non-intestinal type sinonasal adenocarcinoma, high-grade carcinomas such as HPV-related multiphenotypic sinonasal carcinoma, NUT carcinoma and SWI/SNF deficient carcinomas, small round blue cell tumors such as teratocarcinosarcoma, neuroendocrine carcinoma and olfactory neuroblastoma, and finally, low grade spindle cell neoplasms such as glomangiopericytoma, biphenotypic sinonasal sarcoma and solitary fibrous tumor.

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OBJECTIVES: To assess malignant transformation rate, non-sinonasal malignancies, and factors contributing to recurrence in patients treated for sinonasal inverted papilloma (SNIP). STUDY DESIGN: Retrospective study. METHODS: We retrospectively reviewed medical records of all patients treated for SNIP (n = 296) between the years 1984-2014 at Helsinki University Hospital. Data from the Finnish Cancer Registry confirmed the number of those patients with sinonasal and non-sinonasal malignancies. RESULTS: Only 2 of 296 (0.7%) patients primarily diagnosed with benign SNIP developed sinonasal cancer in a mean follow-up of 5.8 years. The most common non-sinonasal cancer sites were similar to those reported for the whole Finnish population. None of the patients presented with an HPV-associated non-sinonasal malignancy. The recurrence rate among patients who underwent attachment-oriented surgery was significantly lower compared to those operated on with other approaches (40.2% vs. 56.6%, p = 0.006). Dysplasia in SNIP was associated with a higher recurrence rate (p < 0.001). CONCLUSIONS: Malignant transformation of SNIP was rare. Patients with SNIP were not prone to HPV-associated non-sinonasal malignancies. Endoscopic resection and attachment-oriented surgery have become predominant approaches in the treatment of SNIP; meanwhile, the total number of SNIP recurrences has decreased. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:506-511, 2023.

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Nasal polyposis (NP) are benign lesion of nasal cavity, affecting up to 1-4% of population. It is known to have up to 70% recurrence rate. The underlying pathophysiology is still undetermined. Recent literatures have thrown light on the viral aetiology for NP. To our knowledge this is the first Indian study done, that aims to evaluate the prevalence of Human papillomavirus (HPV) in NP. It was a prospective case control study done among 40 individuals with NP and 40 healthy controls in a tertiary care centre. All the patients were subjected to routine clinical evaluation, investigations prior to proposed surgeries. The mucosal samples after the surgery were subjected to HPV DNA analysis by RT-PCR. Among the cases, the male to female ratio was 1.3:1. The mean age of patients with NP was 39 ± 14.6. The mean serum IgE levels among the case were 154 IU/ml and was significantly higher as compared to controls. Other inflammatory markers such as absolute eosinophil count, erythrocyte sedimentation rate, and neutrophil to leukocyte ration were found to be not significant. There was no HPV DNA detected among both case as well as controls. There seems to be strong association of IgE and NP, suggesting an IgE mediated pathway for its Causation. There is no association of HPV in NP.

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Purpose of review: The sinonasal tract is home to a uniquely heterogenous collection of malignant tumors. Human papillomavirus (HPV) has been detected in a number of these, but the virus' role as an oncogenic driver or coincidental finding remains unclear. We aim to highlight five sinonasal tumor types and synthesize the prevalence, etiologic role, and known clinicopathologic relevance of HPV in each. Recent findings: The last decade has seen an expansion of investigation into HPV's oncogenic and prognostic significance within sinonasal malignancies. The sinonasal tract poses challenges to HPV detection where p16 lacks value as an accurate surrogate. A growing body of data supports a potentially favorable clinical profile for certain sinonasal HPV-positive lesions. Summary: HPV represents a potential biologically and clinically relevant factor for some sinonasal malignancies. Definitive conclusions regarding HPV's role as a potential oncogenic agent require routine testing using validated methodologies, genomic interrogation, and large-scale prospective studies.

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OBJECTIVES: To examine the epidemiology, subtypes, trends over time, and predictive factors for recurrence and malignant transformation of sinonasal papillomas. METHODS: A retrospective chart review of 118 patients with sinonasal papillomas from 2009 to 2019 was conducted at the University of California, Los Angeles. This study is a follow-up to a previously published study from 2000 to 2009 at the same academic center. RESULTS: The mean age was at presentation was 58.5 years, with a 2:1 male to female ratio, and average follow-up of 30.1 months. The rate of recurrence after complete resection was 19% with an average of 32.6 months to recurrence. The time to recurrence followed a bimodal distribution with 57% of cases recurring within 24 months (mean = 10) and 43% from 40 to 103 months (mean = 61). The proportion of the inverted papillomas rose from 38% in 2000-2004 to 89.6% in 2015-2019. Patients presenting at a younger age had a higher chance of recurrence (mean age 52 with recurrence vs. 61 without recurrence). Age did not correlate with histopathologic transformation in surgical pathology. Furthermore, histopathological transformation did not raise the chance of recurrence. Smoking, alcohol use, chronic rhinosinusitis, and allergic rhinitis were not associated with any of the outcome measures in this study. The most significant factor predicting recurrence, beside age at presentation, was the history of two or more prior sinus surgeries for papillomas or other reasons (OR = 3.52 and 5.81). CONCLUSION: This study explored the features of sinonasal papillomas as well as the risk factors for recurrence and transformation. Younger age at presentation and two or more prior surgeries for papillomas were associated with recurrence. Time to recurrence followed a bimodal distribution, with late recurrences happenning from 40 to 103 months after surgery, emphasizing the importance of long-term follow-up for timely resection of tumors and prevention of malignancy.

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Sinonasal non-intestinal type adenocarcinoma (non-ITAC) is a heterogeneous category that may benefit from improved taxonomy. With the recognition that most non-ITAC are phenotypically seromucinous, stratification may be improved by applying salivary type morphologic criteria and molecular findings. We report two cases of papillary seromucinous adenocarcinoma with sinonasal papilloma-like surface components that show histologic and molecular features analogous to the salivary sialadenoma papilliferum family of tumors. Case 1 concerns a 50-year-old female who presented with a left anterior nasoethmoid polyp, while case 2 is that of a 74 year old female with nasal polyposis. Histologically, both cases demonstrated a surface transitional sinonasal papilloma-like component (more prominent in case 2) with a deeper bilayered glandular component showing papillary and tufted micropapillary growth of monomorphic columnar to cuboidal cells with eosinophilic cytoplasm. Case 1 also showed a deep cribriform/microcystic component. Immunostains showed a delimiting p63/p40 positive basal layer around the SOX-10 positive glandular elements, while the transitional sinonasal papilloma-like components were diffusely p63/p40 positive. Like sialadenoma papilliferum and related tumors, both cases demonstrated BRAF p.V600E mutations in both components and no other alterations. The patients remain disease free at 9 and 19 months respectively. Our cases illustrate a novel sinonasal lesion and suggest that improved morphologic and molecular categorization may refine and reduce the category of non-ITAC.

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OBJECTIVE: Inverted papilloma (IP) is the most common benign neoplasm of the nasal cavity with known risk of recurrence. There is no standardized approach to definitive treatment for attachment sites. This systematic review aims to determine whether surgeon choice of technique differs by anatomic attachment site and whether different surgical techniques contribute to reduced rates of recurrence. DATA SOURCES: PubMed and Ovid Medline. REVIEW METHODS: A systematic review was conducted for studies reporting on IP. Those that included IP recurrence rates and primary tumor attachment site were reviewed. RESULTS: Of 122 published studies, 14 met eligibility criteria, representing 585 patients and a recurrence rate of 5.8%. The maxillary sinus (50.9%) was the most common primary attachment site, and the sphenoid sinus was associated with the highest rate of recurrence (10.4%). The most utilized technique included debulking the tumor, removing mucosa over the attachment site, and drilling the underlying bone. The most common Krouse stage represented was T3 (53.3%). No single technique predicted a propensity for recurrence, but certain techniques are favored depending on IP attachment site. Finally, frozen sections to obtain evidence of clear margins intraoperatively significantly reduced rates of recurrence (3.4% vs 7.3%, P = .045). CONCLUSION: Based on the current literature, the most common technique to address site of attachment involves resecting mucosa and drilling the tumor base. Choice of technique appears to differ for various sites of attachment. Use of intraoperative frozen section analysis appears to be associated with decreased recurrence overall. LEVEL OF EVIDENCE: 3.

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We explored somatic mutations in dysplastic sinonasal inverted papilloma (SNIP), SNIP with concomitant sinonasal squamous cell carcinoma (SNSCC), and SNSCC without preceding SNIP. Ten SNIP and SNSCC samples were analyzed with exome sequencing and tested for human papillomavirus. The identified mutations were compared to the most frequently mutated genes in head and neck squamous cell carcinoma (HNSCC) in the COSMIC database. Exome sequencing data were also analyzed for mutations not previously linked to SNSCC. Seven of the most commonly mutated genes in HNSCC and SNSCC in COSMIC harbored mutations in our data. In addition, we identified mutations in 23 genes that are likely to contribute to SNIP and SNSCC oncogenesis.

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OBJECTIVES: The present study aimed to evaluate human papillomavirus (HPV) occurrence in sinonasal inverted papilloma (SNIP), and to assess factors associated with HPV positivity and SNIP recurrence. STUDY DESIGN: Prospective study. METHODS: We prospectively collected clinical data and fresh tissue specimens from 90 consecutive patients treated for SNIP at Helsinki University Hospital, between 2015 and 2019. Fourteen patients with recurrent SNIP underwent repeated tumor sampling. All tissue specimens were analyzed for the presence of HPV. Factors associated with SNIP recurrence and HPV positivity were assessed. RESULTS: Among 107 SNIP specimens, 14 (13.1%) were positive for low-risk HPV and 6 (5.6%) were positive for high-risk HPV. HPV positivity was associated with an increased risk of recurrence (P = .004). Smoking was significantly associated with HPV positivity in SNIP (P = .01), but a history of HPV-related diseases or patient sexual habits did not correlate with HPV positivity. The recurrence rate was lower among patients with SNIP that underwent an attachment-oriented resection, compared to patients treated without attachment-oriented resections (78.6% vs 25.8%, P < .001). CONCLUSIONS: The risk of SNIP recurrence was highly associated with 1) HPV positivity and 2) surgery without an attachment-oriented resection. Oncogenic HPV was rare in SNIP. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1714-1718, 2022.

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Inverted papilloma (IP) is a common proliferation of squamous epithelial cells of the sinonasal tract. Although considered benign, IP is known to cause local destruction, has a high rate of recurrence, and a low, but significant rate of malignant transformation. Differentiating an IP from its histologic mimickers is essential for appropriate risk stratification and long-term surveillance. A classic case of sinonasal inverted papilloma is discussed.

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