Loss of p16 expression is a risk factor for recurrence in sinonasal inverted papilloma.

BACKGROUND: The purpose of this study was to evaluate p16, p53, EGFR, pEGFR protein expression and HPV infection as possible markers of tumor progression in a series of sinonasal inverted papilloma (SNIP) and sinonasal squamous cell carcinoma (SNSCC). METHODS: A series of 49 SNIP, 11 SNSCC associated with SNIP (SNIP-SNSCC) and 52 SNSCC not associated with SNIP were analyzed for p16, p53, EGFR, and phosphorylated EGFR (pEGFR) expression by immunohistochemistry. Human papillomavirus (HPV) infection status was evaluated by DNA-PCR. Results were correlated to clinical and follow-up data. RESULTS: Reduced or loss of p16 expression was observed in 18% SNIP, 64% SNIP-SNSCC and 87% of SNSCC. Reduced or loss p16 staining in SNIP correlated with shorter recurrent SNIP-free follow-up. In contrast, p16 expression was not predictive of recurrent SNSCC in cases with SNIP-SNSCC and SNSCC. P53, EGFR, and pEGFR expression did not differ between the tumor groups, nor were they related to recurrent SNIP-free follow-up or recurrent SNSCC. Oncogenic HPV types 16 and 18 were detected in 5% of SNIP and 18% of SNIP-SNSCC, but not in SNSCC. There was no correlation between HPV infection and >70% p16 immunostaining. CONCLUSIONS: HPV infection appears to play a minor role in SNIP and SNSCC and p16 immunostaining does not appear a valid surrogate marker for HPV. However, reduced or loss p16 expression may have prognostic value as a risk marker for recurrent SNIP.

Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma-An Even Broader Tumor Entity?

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a recently defined tumor subtype with apparent favorable clinical outcome despite aggressive histomorphology. However, in recent years, additional numbers of cases, with more variable features and at locations outside the sinonasal region, have complicated the definition of HMSC. Here, we have performed a systematic review of all cases described so far in order to accumulate more knowledge. We identified 127 articles published between 2013 and 2021, of which 21 presented unique cases. In total, 79 unique patient cases were identified and their clinical and micromorphological nature are herein summarized. In our opinion, better clinical follow-up data and a more detailed tumor characterization are preferably needed before HMSC can finally be justified as its own tumor entity.

Human papillomavirus-related multiphenotypic sinonasal carcinoma: a clinico-pathological dilemma case report.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC), is a new entity that is restricted to the sinonasal tract and is associated with high-risk HPV. This tumor is suggested to have an indolent behavior with a better prognosis than other carcinomas. We report a unique case of HMSC with a locally aggressive behavior. It is about a 61-year-old men presented with 12 months of unilateral progressive olfactory dysfunction accompanied by exophthalmia of the left eye, declining vision and headaches for 6 months. Computed tomography imaging revealed a voluminous mass occupying the ethmoid, maxillary and frontal sinus with bony destruction of the left ethmoidal blade. Histology showed a tumor composed of variably sized nests, separated by thick mucoid stroma. Tumor cells are plasmacytoid with hyperchromatic nuclei and frequent mitoses. Immunohistochemistry revealed that these cells were positive for cytokeratin AE1/AE3, p16 and negative for CK7, CK20, CD117, p40, p63, S100, synaptophysin and chromogranin.

PD-L1 expression, tumor-infiltrating lymphocytes, mismatch repair deficiency, EGFR alteration and HPV infection in sinonasal squamous cell carcinoma.

The antitumor efficacies of immune checkpoint inhibitors (ICIs) and the usefulness of potential predictive markers such as programmed death-ligand 1 (PD-L1) expression, density of tumor-infiltrating lymphocytes (TILs) and microsatellite instability (MSI) in sinonasal squamous cell carcinoma (SNSCC) have not been fully elucidated. We retrospectively analyzed 131 SNSCCs with immunohistochemistry for PD-L1 expression, TIL subpopulations and loss of mismatch repair (MMR) proteins as a surrogate for MSI-high. We also comprehensively evaluated the mutual relationships among these immuno-markers, high-risk human papillomavirus (HPV) infection, epidermal growth factor receptor (EGFR) gene status, and KRAS mutation. PD-L1 expression (tumor proportion score ≥ 1%) was detected in 60 (45.8%) SNSCC cases and was significantly associated with worse overall survival (OS) (p = 0.0240). High density of cluster of differentiation 8 (CD8)-positive TILs was significantly associated with better progression-free survival (PFS) (p = 0.0368), and high density of forkhead box protein P3-positive TILs was significantly associated with better PFS and OS (p = 0.0007 and 0.0143, respectively). With respect to the combination of CD8 + TIL and PD-L1 expression, the high-CD8/PD-L1-negative group showed the most favorable prognosis, whereas the low-CD8/PD-L1-positive group showed the worst prognosis. MMR loss was detected in 3 (2.3%) of the 131 cases. HPV infection (6.1%), EGFR mutation (14.5%), EGFR copy number gain (26%), and MMR loss were essentially mutually exclusive; patients in these molecular groups showed significant differences in prognosis but not in the degree of PD-L1 expression or TILs. Among the nine ICI-treated patients, three (33.3%) were responders, and the EGFR-wild type cases (n = 7) showed better clinical responses to an ICI compared to the EGFR-mutant cases (n = 2). Among the patients with residual/recurrent EGFR-wild type tumors (n = 43), ICI treatment significantly improved OS (p = 0.0281). The results suggest that the evaluation of immuno-markers and molecular subclassification may be helpful for prognostic prediction and selecting an individualized therapeutic strategy for patients with SNSCC.

Clinicopathologic Significance of EGFR Mutation and HPV Infection in Sinonasal Squamous Cell Carcinoma.

Sinonasal squamous cell carcinoma (SNSCC) is sometimes associated with high-risk human papillomavirus (HR-HPV) infection and inverted sinonasal papilloma or oncocytic sinonasal papilloma. Frequent mutations of EGFR and KRAS are reported in inverted sinonasal papilloma-related sinonasal squamous cell carcinoma (ISP-SCC) and oncocytic sinonasal papilloma-related SNSCC, respectively. Here, we attempted to determine the prevalence and the prognostic significances of these alterations in SNSCC. We retrospectively collected 146 SNSCCs, including 14 ISP-SCCs, and comprehensively analyzed the HR-HPV infection by human papillomavirus (HPV)-RNA in situ hybridization, EGFR gene copy number gain (CNG) by chromogenic in situ hybridization, and gene mutations in EGFR and KRAS by Sanger sequencing. HR-HPV was detected in 11 cases (7.5%), whereas all 14 ISP-SCCs were negative. EGFR mutations were present in 21 (14.7%) of 143 SNSCCs, including 13/14 (92.9%) ISP-SCCs and 8/129 (6.2%) non-ISP-SCCs (P<0.0001). The majority of EGFR mutations were exon 20 insertions, with the remainder composed of deletions and single-nucleotide substitutions in exons 19 and 20. All of 142 SNSCCs harbored no KRAS mutation. EGFR CNG was detected in 41 (28.1%) of 146 SNSCCs; all of them were HPV negative and 3 had EGFR mutations. Collectively, EGFR mutation, EGFR CNG, and HR-HPV were essentially mutually exclusive, and each subgroup had distinct clinicopathologic features. The HPV-negative/EGFR-mutant group, the HPV-negative/EGFR CNG-positive group, and the triple-negative group had significantly worse prognoses than the HPV-positive group (P=0.0265, 0.0264, and 0.0394, respectively). In conclusion, EGFR mutation may play a pathogenetically important role in some populations of SNSCCs, especially ISP-SCCs. The molecular subclassification of SNSCCs may contribute to prognostic prediction and molecular-targeted precision medicine.

HPV-Related Multiphenotypic Sinonasal Carcinoma: A Case Report and Literature Review.

OBJECTIVES: Human papilloma virus-related multi phenotypic sinonasal carcinoma (HMSC), a recently characterized sinonasal malignancy, is discussed including histology, clinical presentation, and treatment outcomes. STUDY DESIGN: Case report with literature review. METHODS: A case of HMSC is reported, as well as a retrospective review of all cases of HMSC reported in the English literature from January 2000 through May 2018 in the MEDLINE, EMBASE, and Scopus databases. Case data from selected articles was pooled along with the presented case and analyzed. RESULTS: Including the present case report, a total of 57 cases of HMSC were identified through literature review. Of the 42 cases with staging information, 25 (60%) presented as early-stage disease (T1/T2). No nodal metastasis or disease-specific mortalities were reported. Among the 44 cases with posttreatment follow-up data, 16 cases (36.4%) developed local recurrence. The majority of recurrences occurred 24 to 60 months posttreatment, although reports of recurrence 10 and 29 years posttreatment exist. Local recurrence occurred in 40% and 60% of patients with perineural invasion and bone invasion, respectively. Patients who developed local recurrence had a longer disease-free interval when treated with adjuvant radiotherapy, which approached statistical significance. CONCLUSIONS: HMSC is a distinct entity with paradoxically aggressive morphology paired with an indolent clinical course characterized by high rates of local recurrence but no reported disease-specific mortalities to date. Surgery with or without adjuvant radiotherapy is the most common treatment modality, and adjuvant radiotherapy may be associated with an increased disease-free interval among patients with local recurrence. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:106-110, 2021.

Association Between Human Papilloma Virus Infection and Malignant Sinonasal Inverted Papilloma.

OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the risk of malignant sinonasal inverted papilloma (SNIP) according to the type of human papilloma virus (HPV) infection. METHODS: The databases of PubMed, EmBase, and Web of Science were searched for studies that reported the risk of malignant SNIP in patients infected by specific types of HPV. The quantitative analyses for pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Twenty-six molecular epidemiological studies that recruited a total of 900 patients with SNIP were selected for the final meta-analysis. The summary ORs indicated that HPV-6 (OR: 2.02; 95% CI: 0.47-8.61; P = .343), HPV-11 (OR: 0.86; 95% CI: 0.26-2.89; P = .806), and HPV-6/11 (OR: 1.44; 95% CI: 0.59-3.53; P = .426) infections were not associated with the risk of malignant SNIP. However, the risk of malignant SNIP was increased in patients infected with HPV-16 (OR: 8.51; 95% CI: 3.36-21.59; P < .001), HPV-11/16 (OR: 7.95; 95% CI: 1.13-56.01; P = .038), HPV-18 (OR: 23.26; 95% CI: 5.27-102.73; P < .001), and HPV-16/18 (OR: 24.34; 95% CI: 5.74-103.18; P < .001). CONCLUSIONS: This study found that patients infected with HPV types 16, 11/16, 18, and 16/18 were associated with an increased risk of malignant SNIP. However, patients infected with HPV types 6, 11, and 6/11 did not have a significant risk of malignant SNIP. Laryngoscope, 131:1200-1205, 2021.

The role of human papillomavirus in the pathogenesis of sinonasal inverted papilloma: a narrative review.

Sinonasal inverted papillomas (IPs) are rare tumours arising from the nasal epithelial mucosa. Most lesions are benign, but a subset of IPs progress to dysplasia and squamous cell carcinoma. Although the epidemiology and clinical features of IPs are well known, the pathogenesis is still unclear. Given the established role of human papillomaviruses (HPVs) in the formation of other mucosal tumours including cervical and oropharyngeal cancer, some have suggested the virus may play a role in IP development. However, the association between HPV and IPs has not yet been proven, and the variable detection of HPV DNA in IPs has cast uncertainty on whether the virus plays a major role in pathogenesis. In this review, we summarize early clinical reports and synthesize recent studies that may elucidate the association between HPV and IPs. We also discuss the role HPV may have in the progression of benign IP to dysplasia and malignancy, as well as potential pathological mechanisms. We hope that synthesizing the initial and recent studies on this topic will not only lead to a better understanding of research in the role of HPV in IP development, but also help guide and contextualize future studies.

Expression of Sp100 Protein in Human Papillomavirus-Associated Sinonasal Inverted Papilloma.

OBJECTIVE: Sinonasal inverted papilloma (SNIP) is a benign tumor characterized by an aggressive growth, a tendency to recur, and an association with malignancy. However, the precise etiology of SNIP is still unknown. The objective of this study was to identify the expression pattern of speckled protein 100 (Sp100) in the malignant transformation (MT) of SNIP and its correlation with human papillomavirus (HPV)-16 and HPV-18 infections and other clinical features. This would further help in understanding the possible mechanisms for the development of SNIP. METHODS: Individual nasal mucosa specimens from 40 patients (25 males and 15 females) and 10 inferior turbinate specimens as controls were included in the present study. The samples were divided into several sections for histopathological examination, HPV DNA detection, and immunohistochemical staining. RESULTS: We observed that as SNIP progressed, the Sp100 protein expression was gradually downregulated, and SP100 localization changed from nucleus to the cytoplasm. Positive rate of HPV infection in the SNIP with MT group was higher than that in the other groups, and Sp100 expression was correlated to HPV infections and SNIP with MT. However, no correlation was observed between Sp100 expression and clinical features, such as age, gender, and smoking. CONCLUSION: Positive rate of HPV infection is high in the SNIP with MT and has a correlation with Sp100 expression. In addition, the expression of Sp100 is downregulated in SNIP with MT, and Sp100 may play a role in the progression of SNIP.

Impact of human papillomaviruses (HPV) on recurrence rate and malignant progression of sinonasal papillomas.

Sinonasal papillomas are characterized by their potential for frequent recurrences and malignant progression. Currently, the role of human papillomavirus (HPV) infection in sinonasal papillomas is unclear. A study was conducted to elucidate the impact of HPV infection on recurrence and malignant progression of sinonasal papillomas. One hundred and seven patients with 151 tumors could be examined. One hundred and one patients suffered from benign papilloma, mostly inverted papillomas (IP); six patients suffered from carcinomas in situ and squamous cell carcinomas (SCC) ex-IP. Recurrent IP were more often HPV-positive than non-recurrent tumors (38.8% vs. 60%-65%). Low-risk (LR) HPV infection (especially HPV 6) increased the risk of tumor recurrences (p = 0.0385 and p = 0.0556, respectively). IP and oncocytic papillomas (both lesions are known for their malignant potential) were more often high-risk (HR) HPV-positive (15.5% and 16.7%) than fungiform papilloma (which usually does not progress to carcinoma). CIS and SCC ex-IP displayed higher HPV rates than benign IP (83.3% vs. 38.8%), especially higher rates of HR-HPV (66.7% vs. 23.8%, p = 0.0415). Data from this study endorse the hypothesis that recurrence of sinonasal papillomas is promoted by LR-HPV infection and that malignant progression of IP is promoted by HR-HPV infection.

Treatment sequence of cetuximab and immune checkpoint inhibitor in head and neck squamous cell carcinoma differentially affects outcomes.

OBJECTIVES: To examine the impact of treatment sequences of Immune checkpoint inhibitor (ICI) and cetuximab on clinical outcomes in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Clinicopathologic data were retrospectively collected on patients with R/M HNSCC who received ICI treatment. Association between treatment sequence and clinical outcomes were assessed. RESULTS: A total of 113 patients with R/M HNSCC were analyzed. Patients who had cetuximab prior to ICI had worse overall (HR, 1.83) and progression-free survival (HR, 1.76) compare to those without prior cetuximab. Among patients who had subsequent therapy after ICI, cetuximab-based therapy was associated with a trend toward higher response rate and longer survival than non-cetuximab regimen. CONCLUSION: Our single institution analysis showed that treatment sequence of cetuximab and ICI in R/M HNSCC may affect clinical outcomes. Cetuximab prior to ICI was associated with worse outcomes while the efficacy of cetuximab may be enhanced after ICI therapy.

Extramedullary plasmacytoma of the nasal cavity and ethmoidal sinus in human immunodeficiency virus-positive patient.

Extramedullary plasmacytoma (EMP) occurring in the nose and paranasal sinus regions are rare with a male preponderance in the fifth and seventh decades of life. We report a case of EMP of the nasal cavity and ethmoid sinus in a 28-year-old female with human immunodeficiency virus infection.

A clinical analysis of sinonasal squamous cell carcinoma: a comparison of de novo squamous cell carcinoma and squamous cell carcinoma arising from inverted papilloma.

Background: Sinonasal squamous cell carcinoma (SCC) is a rare tumor arising either de novo or in association with inverted papillomas (IPs).Objectives: The aim of this study was to investigate and compare the oncological features and prognosis of patients with sinonasal SCCs based on their etiology.Material and methods: The medical records of 117 patients who had been diagnosed with de novo SCC or those arising from IP (IP-SCC) were retrospectively reviewed. In situ hybridization analyses to detect HPV 16/18DNA and p16 immunohistochemistry were also performed in 10 cases with IP-SCC.Results: The three-year disease-specific survival (DSS) rate was higher in cases with T1, 2 and 3 than in cases with T4 in both tumor groups. T4 cases with de novo SCC had a better DSS than those with IP-SCCs. HPV16/18 was not detected in any of the 10 IP-SCCs.Conclusions and significance: T4 cases with de novo SCC tended to have a better DSS than those with IP-SCC. Since some T4 patients with IP-SCC were found to have a highly aggressive disease, careful treatment planning should be performed. High-risk HPV may not play a vital role in the carcinomatous transformation of most IP-SCC cases.

Identification of Rare and Common HPV Genotypes in Sinonasal Papillomas.

Sinonasal papillomas are rare, usually benign tumors arising from the Schneiderian membrane. Human papillomaviruses (HPV) can infect differentiating skin and mucosal cells and can induce uncontrolled growth patterns. Their effect on development of sinonasal papillomas has been discussed controversially in recent years. A monocentric, retrospective study was conducted to investigate histopathologic features of sinonasal papillomas and to establish an assay for HPV detection and genotyping in papillomas. Schneiderian papillomas are divided into three groups according to histopathologic features: the largest group are inverted papillomas, followed by fungiform (exophytic) and oncocytic papillomas. HPV screening was performed with high sensitivity by PCR employing My09/11 and 125 consensus primers. Adding a third primer pair (GP5+/GP6+) d increase sensitivity. Reverse hybridization microarrays achieved HPV genotyping better than pyrosequencing in our setting. HPV infection rates were higher in papillomas (46.7%) than infection rates reported for healthy mucosa (up to 13%). P16(INK4a) was not a reliable surrogate marker for HPV infection in sinonasal papillomas. Data from our study endorses the hypothesis that HPV infection promotes formation of sinonasal papillomas. However, apart from HPV genotypes that are frequently found in e.g. anogenital lesions (such as 6, 11, or 16), tissue samples of sinonasal papillomas also displayed infection with "rare" HPV types (such as 58, 42, 83, or 91).

High prevalence of human papillomavirus infection in sinonasal inverted papilloma: a single-institution cohort of patients.

BACKGROUND: Both the prevalence of sinonasal inverted papilloma (IP) and the causal association with alpha-human papillomaviruses (alpha-HPVs) are controversial. In this study we aimed to determine HPV status in histologically selected, microdissected, formalin-fixed, and paraffin-embedded tissue samples of IP. METHODS: HPV status was assessed retrospectively by polymerase chain reaction (PCR)-bead-based multiplex genotyping on tissue samples of patients diagnosed with IP and consecutively treated with endoscopic resection. Forty-one HPV genotypes were considered, distinguishing between high risk and low risk. HPV status was correlated with demographics and clinical variables. Sixty sinonasal IP tissue samples were initially considered. After exclusion of 5 cases due to insufficient quality/quantity of the samples, 55 patients were included for analysis. RESULTS: HPV-DNA sequences were identified in 34 of 55 (61.8%) IPs, with a higher prevalence of high-risk than low-risk HPV genotypes (19 [55.9%] and 15 cases [44.1%], respectively). HPV16 strongly prevailed among the high-risk HPV cases (84.2%), and HPV54 prevailed among the low-risk HPV cases (53.3%). IPs with origin within the maxillary sinus were significantly associated with high-risk HPV (p = 0.019). No significant associations emerged between HPV status and demographics or clinical variables. CONCLUSION: In a series of 55 IP tissue samples, HPV-DNA sequences were identified in 61.8% of cases, which differs from the data of previous investigations. Further case-control studies are advocated to confirm this prevalence in the Italian population addressed, and also to clarify any pathogenic involvement of HPV in the natural history of IPs.

Human Papillomavirus and Factors Associated with Recurrence in Sinonasal Inverted Papillomas from Poland and Spain.

Sinonasal inverted papilloma (SNIP) is a benign but locally aggressive tumor that has a tendency for recurrence and malignant transformation. The role of human papillomavirus (HPV) in SNIP is controversial. To determine the HPV-DNA prevalence and type distribution in SNIP in two different geographic areas and assess the association between SNIP recurrence and HPV infection, as well as additional potential etiologic factors. Two retrospective cohorts of SNIP patients from Poland and Spain were evaluated. Demographic, tobacco/alcohol use, clinical, and follow-up data were collected. All samples were subject to histopathologic evaluation, DNA quality control, and HPV-DNA detection by PCR. HPV-DNA positive samples and a random sample of HPV-DNA negative cases were further subject to p16INK4a analysis. Proportional-hazards models were used to evaluate the risk of recurrence by selected variables. Seventy-nine SNIP patients (46 from Spain diagnosed between 1995 and 2014, and 33 from Poland diagnosed between 2012 and 2017) were included in the study. HPV-DNA was detected in four patients (5.1%), two from each region, and all four were positive for the HPV11 subtype. Seventeen patients (21.5%) experienced recurrence, with a median time to recurrence of 14 months. No association was identified between lesional HPV-DNA positivity, toxic habits, Krouse stage, or malignant transformation and a higher risk of recurrence. The low prevalence of HPV-DNA in SNIPs suggests that HPV is not a main etiology for development of these lesions. With a lack of association between the evaluated factors and recurrence, further research with larger number of patients and additional biomarkers is warranted to further understand predisposing risk factors.

Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma: A Recent Discovery. A Case Report and Literature Review.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma is a distinct, recently described neoplasm of salivary gland nature that has an unusual microscopic appearance exhibiting multidirectional differentiation. Originally described by Bishop et al. in 2012, this distinct form of head and neck cancer is a very rare entity that few pathologists have encountered in practice, and only 50 cases have been reported in the literature. It usually presents as a large, destructive mass confined to the nasal cavity or paranasal sinuses, and is always associated with high-risk HPV infection. Although histologically it often resembles adenoid cystic carcinoma, this neoplasm also consistently exhibits features of myoepithelial, ductal and squamous differentiation. Newly recognized characteristics have recently been described that include bizarre pleomorphism, sarcomatoid transformation, and heterologous cartilaginous differentiation. These unique features have continued to expand the morphologic spectrum of this neoplasm and justify the recent change in its nomenclature from "HPV-related carcinoma with adenoid cystic-like features" to "HPV-related multiphenotypic sinonasal carcinoma (HMSC)". In 2017, "HPV-related carcinoma with adenoid cystic like features" was included as a provisional tumor type by the World Health Organization Classification of Head and Neck Tumors. Despite the presence of high-grade histologic characteristics such as necrosis and brisk mitotic activity, and a tendency for recurrence, HMSC demonstrates indolent clinical behavior and carries a good prognosis.

Don't stop the champions of research now: a brief history of head and neck pathology developments.

The field of head and neck pathology was just developing 50 years ago but has certainly come a long way in a relatively short time. Thousands of developments in diagnostic criteria, tumor classification, malignancy staging, immunohistochemistry application, and molecular testing have been made during this time, with an exponential increase in literature on the topics over the past few decades: There were 3506 articles published on head and neck topics in the decade between 1969 and 1978 (PubMed source), with a staggering 89266 manuscripts published in the most recent decade. It is daunting and impossible to narrow the more than 162000 publications in this field and suggest only a few topics of significance. However, the breakthrough in this anatomic discipline has been achieved in 3 major sites: oropharyngeal carcinoma, salivary gland neoplasms, and sinonasal tract tumors. This review will highlight selected topics in these anatomic sites in which the most profound changes in diagnosis have occurred, focusing on the information that helps to guide daily routine practice of surgical pathology.