A review of current biomarkers in chronic rhinosinusitis with or without nasal polyps.

INTRODUCTION: Chronic rhinosinusitis (CRS) is a heterogeneous disease with a variety of cellular and molecular pathophysiologic mechanisms. Biomarkers have been explored in CRS using various phenotypes, such as polyp recurrence after surgery. Recently, the presence of regiotype in CRS with nasal polyps (CRSwNP) and the introduction of biologics for the treatment of CRSwNP has indicated the importance of endotypes, and there is a need to elucidate endotype-based biomarkers. AREAS COVERED: Biomarkers for eosinophilic CRS, nasal polyps, disease severity, and polyp recurrence have been identified. Additionally, endotypes are being identified for CRSwNP and CRS without nasal polyps using cluster analysis, an unsupervised learning technique. EXPERT OPINION: Endotypes in CRS have still being established, and biomarkers capable of identifying endotypes of CRS are not yet clear. When identifying endotype-based biomarkers, it is necessary to first identify endotypes clarified by cluster analysis for outcomes. With the application of machine learning, the idea of predicting outcomes using a combination of multiple integrated biomarkers, rather than a single biomarker, will become mainstream.

Dupilumab improves eosinophilic otitis media associated with eosinophilic chronic rhinosinusitis.

BACKGROUND: Eosinophilic otitis media (EOM) is a refractory condition associated with eosinophilic chronic rhinosinusitis and bronchial asthma. EOM is characterized by type-2 inflammation and is refractory to various treatments. We investigated the efficacy of dupilumab, interleukin-4 receptor alpha antagonist, for patients with EOM complicated by eosinophilic chronic rhinosinusitis (ECRS). METHODS: Between April 2017 and April 2022, we treated 124 patients with dupilumab for refractory CRS or bronchial asthma. Of these, 14 had EOM concurrently, and 10 of them who had been treated for >6 months were included in our study. We retrospectively evaluated the efficacy of dupilumab by the amount of systemic corticosteroid used, the frequency of exacerbations, severity score of EOM, computed tomography (CT) score of temporal bones, and pure tone audiometry. We also enrolled 8 EOM patients without dupilumab treatment as a control group. RESULTS: Dupilumab significantly improved the amount of systemic corticosteroid used and the frequency of exacerbation and compared with before dupilumab was used (p = 0.01 and <0.01, respectively). All patients could be weaned from systemic-corticosteroid therapy by 54 weeks of dupilumab use. The severity score of EOM and CT score for temporal bones were significantly lower than before the treatment (p = 0.01 and 0.01, respectively). Compared to the control group, the systemic corticosteroid used and severity scores were improved in the dupilumab group (p = 0.02 and < 0.01, respectively). CONCLUSIONS: Dupilumab could be used to wean patients from systemic corticosteroids with the improvement of severity score in EOM associated with ECRS and bronchial asthma.

Inflammatory molecular endotypes of nasal polyps derived from White and Japanese populations.

BACKGROUND: Emerging evidence suggests that chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with disparate inflammatory characteristics between different racial groups and geographies. Currently, little is known about possible underlying distinguishing factors between these inflammatory differences. OBJECTIVE: Our aim was to interrogate differences in CRSwNP disease between White/non-Asian patients and Japanese patients by using whole transcriptome and single-cell RNA gene expression profiling of nasal polyps (NPs). METHODS: We performed whole transcriptome RNA sequencing with endotype stratification of NPs from 8 White patients (residing in the United States) and 9 Japanese patients (residing in Japan). Reproducibility was confirmed by quantitative PCR in an independent validation set of 46 White and 31 Japanese patients. Single-cell RNA sequencing (scRNAseq) was used to stratify key cell types for contributory transcriptional signatures. RESULTS: Unsupervised clustering analysis identified 2 major endotypes that were present within both cohorts of patients with NPs and had previously been reported at the cytokine level: (1) type 2 endotype and (2) non-type 2 endotype. Importantly, there was a statistically significant difference in the proportion of these endotypes between these geographically distinct subgroups with NPs (P = .03). Droplet-based single-cell RNA sequencing further identified prominent type 2 inflammatory transcript expression: C-C motif chemokine ligand 13 (CCL13) and CCL18 in M2 macrophages, as well as cystatin SN (CST1) and CCL26 in basal, suprabasal, and secretory epithelial cells. CONCLUSION: NPs from both racial groups harbor the same 2 major endotypes, which we have determined to be present in differing ratios between each cohort with CRSwNP disease. Distinct inflammatory and epithelial cells contribute to the type 2 inflammatory profiles observed.

Comparison of Current Staging Systems for Sinonasal Inverted Papilloma.

BACKGROUND: A staging system is essential for determining the optimal surgical approach and predicting postoperative outcomes for inverted papilloma (IP). Although staging systems based on the extent to which the location is occupied by an IP have been widely used, an origin site-based classification of IP using unsupervised machine learning algorithms has recently been reported. OBJECTIVE: To determine the most appropriate of five staging systems for sinonasal IP by comparing recurrence rates for each stage according to each of those systems. METHODS: Eighty-seven patients with sinonasal IP were enrolled in the study. Their tumors were retrospectively categorized according to the Krouse, Oikawa, Cannady, and Han staging systems, which are based on the extent of IP, and the Meng system, which is based on the site of origin. The rates of recurrence for each stage of the five systems were compared. RESULTS: Seven of the 87 patients (8.0%) had recurrences during an average 45.5 months (12-138 months) of follow-up. There were significant differences in disease-free survival between the stages specified by Han and Meng (p = 0.027 and p < 0.001, respectively), but not between the stages specified by Krouse, Oikawa, and Cannady (p = 0.236, 0.062, and 0.130, respectively). Cox proportional hazard models revealed that Meng system (adjusted hazard ratio [aHR] 4.32, 95% confidence interval [CI] 1.10-17.04) and presence of dysplasia (aHR 7.42, 95% CI 1.15-47.85) were significantly associated with recurrence. CONCLUSION: The staging systems proposed by Han and Meng were found to be accurate in terms of tumor recurrence. We recommend use of the Han staging system before surgery and the Meng system after intraoperative identification of the origin of the tumor.

Prelacrimal approach vs conventional surgery for inverted papilloma in the maxillary sinus.

BACKGROUND: The prelacrimal approach, termed endoscopic modified medial maxillectomy (EMMM), has recently been applied for treatment of inverted papilloma (IP) in the maxillary sinus. EMMM provides wider access to the maxillary sinus while preserving the inferior turbinate and nasolacrimal duct. METHODS: We reviewed patients with IP in the maxillary sinus to compare the surgical results obtained by conventional surgery (ie, endoscopic maxillary sinus antrostomy or in combination with the Caldwell-Luc approach) with those obtained by EMMM. RESULTS: All patients had a T3 on the Krouse staging system, and the average follow-up time was 46.0 months. Of the 18 patients in the conventional group, recurrence was seen in 3 patients (16.6%). No recurrence was seen in the 27 patients who showed preservation of the inferior turbinate and nasolacrimal duct, and no complications occurred in the EMMM group. CONCLUSIONS: EMMM is an effective surgical approach that reduces recurrence with fewer complications.

Serum IgG4 as a biomarker reflecting pathophysiology and post-operative recurrence in chronic rhinosinusitis.

BACKGROUND: Type 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS. METHODS: Association between the serum IgG4 levels and clinicopathological factors was analyzed in 336 CRS patients. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of serum IgG4 levels that can be used to predict the post-operative recurrence. RESULTS: Serum IgG4 levels were significantly higher in patients with moderate to severe ECRS versus those with non to mild ECRS. The levels were also significantly higher in asthmatic patients and patients exhibiting recurrence after surgery compared to controls. ROC analysis determined that the best cut-off value for the serum IgG4 level to predict the post-operative recurrence was 95 mg/dL. The corresponding sensitivity and specificity were 39.7% and 80.5%, respectively. When we combined the two cut-off values for the serum IgG4 and periostin, patients with high serum levels of either IgG4 or periostin exhibited a high post-operative recurrence (OR: 3.95) as compared to patients having low serum levels of both IgG4 and periostin. CONCLUSIONS: The present results demonstrate that the serum IgG4 level is associated with disease severity and post-operative course in CRS. In particular, the combination of serum IgG4 and periostin could be a novel biomarker that predicts post-operative recurrence.

JESREC score and mucosal eosinophilia can predict endotypes of chronic rhinosinusitis with nasal polyps.

OBJECTIVE: Recently, JESREC score and mucosal eosinophil count have been used to diagnose eosinophilic chronic rhinosinusitis (ECRS) in Japan. However, it remains unknown whether the subtypes of CRS diagnosed by these criteria have different endotypes. In the present study, we investigated whether JESREC score and mucosal eosinophil count were appropriate for classification of CRS subgroups into endotypes. METHODS: A cross-sectional study involving 71 consecutive patients with CRS with nasal polyps (CRSwNP) and 13 control patients was performed. Nasal polyp tissues from CRSwNP patients and uncinate process tissues from control patients were collected for analysis of inflammatory cells by immunohistochemistry and measurement of cytokines and chemokines by ELISA and quantitative real-time PCR. We compared the differences between subtypes according to JESREC score and mucosal eosinophil count and investigated the subgroups with different endotypes by cluster analysis and principal component analysis. RESULTS: In the 71 CRSwNP patients, 9 patients had JESREC score <11 and mucosal eosinophil count <70/HPF (Group A), 20 patients had JESREC score ≥11 and mucosal eosinophil count <70/HPF (Group C), and 42 patients had JESREC score ≥11 and mucosal eosinophil count ≥70/high-power field (HPF) (Group D). Semiquantitative analysis of inflammatory cells showed that eosinophils, neutrophils, macrophages, mast cells, and basophils differed significantly between the subgroups. At the mRNA level, CLC, IL5, IL13, CCL11, CCL24, CCL26, POSTN, CSF3, and IL8 showed significant differences. At the protein level, eotaxin-2/CCL24, eotaxin-3/CCL26, and G-CSF had significant differences. Cluster analysis using gene expression levels in 55 CRS patients and 11 control patients revealed that the patients could be classified into five clusters. Cluster 1 (n=27) contained all patients with Group D. Cluster 2 (n=11) comprised all control patients. Cluster 3 (n=4) included mixed subtypes: one with Group A and three with Group D. Cluster 4 (n=7) and Cluster 5 (n=17) contained all patients with Groups A and C, respectively. Furthermore, the principal component analysis revealed that the subtypes had different characteristics. CONCLUSION: CRS subtypes based on JESREC score and mucosal eosinophil count showed different inflammatory patterns, and unsupervised statistical analyses supported the classification that can predict endotypes. From these results, we concluded that the classification based on JESREC score and mucosal eosinophil count was useful for predicting CRS endotypes.

Prognostic value of C-reactive protein/albumin ratio for patients with hypopharyngeal and laryngeal cancer undergoing invasive surgery involving laryngectomy.

BACKGROUND: The C-reactive protein/albumin (CRP/Alb) ratio has been recently established as a prognostic indicator in various cancer types. However, few reports regarding the prognostic value of the CRP/Alb ratio in head and neck cancer exist. This study aimed to investigate the significance of the CRP/Alb ratio in clinical outcomes after invasive surgery involving laryngectomy for hypopharyngeal and laryngeal cancer. METHODS: We evaluated 56 patients who underwent total laryngectomy or total pharyngolaryngectomy between 2003 and 2012. Univariate and multivariate analyses were retrospectively performed to examine the prognostic value of the CRP/Alb ratio in these patients. RESULTS: The optimal cutoff value of the CRP/Alb ratio was 0.32. Multivariate analysis showed that the CRP/Alb ratio was a significant and independent predictor of poor overall and disease-free survival. CONCLUSION: The CRP/Alb ratio may be a novel and useful indicator for predicting postoperative outcomes in patients with hypopharyngeal and laryngeal cancer.

The role of ADAM-like decysin 1 in non-eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is classified into two subtypes: eosinophilic (ECRSwNP) and non-eosinophilic (NECRSwNP). Although the inflammatory patterns of ECRSwNP have been elucidated, NECRSwNP is poorly understood. AIMS/OBJECTIVES: The metalloproteinase ADAM-like decysin 1 (ADAMDEC1) has been reported to play a role in the early stages of the inflammatory response. We investigated the role of ADAMDEC1 in the pathogenesis of CRSwNP. MATERIAL AND METHODS: We compared ADAMDEC1 expression in nasal polyp tissue from CRS patients using immunohistochemistry and RT-qPCR. Macrophages were cultured and ADAMDEC1 expression was determined at baseline and after exposure to lipopolysaccharide (LPS). RESULTS: ADAMDEC1 was virtually undetectable in tissues from control patients but was highly expressed in the NECRSwNP group compared with the ECRSwNP group. In nasal polyp tissues, ADAMDEC1 was expressed by CD68-positive cells, with a positive correlation between ADAMDEC1-positive and CD68-positive cells, and also between ADAMDEC1 and CD68 mRNA levels. Furthermore, stimulation of monocyte-derived macrophages with LPS induced ADAMDEC1 expression. CONCLUSIONS AND SIGNIFICANCE: This study demonstrates that ADAMDEC1 is involved in the pathogenesis of NECRSwNP, and also bacterial endotoxin signalling in macrophages; however, the underlying mechanism remains to be elucidated.

Assessment of suitable reference genes for RT-qPCR studies in chronic rhinosinusitis.

Reverse transcription-quantitative polymerase chain reaction is a valuable and reliable method for gene quantification. Target gene expression is usually quantified by normalization using reference genes (RGs), and accurate normalization is critical for producing reliable data. However, stable RGs in nasal polyps and sinonasal tissues from patients with chronic rhinosinusitis (CRS) have not been well investigated. Here, we used a two-stage study design to identify stable RGs. We assessed the stability of 15 commonly used candidate RGs using five programs-geNorm, NormFinder, BestKeeper, ΔCT, and RefFinder. Ribosomal protein lateral stalk subunit P1 (RPLP1) and ribosomal protein lateral stalk subunit P0 (RPLP0) were the two most stable RGs in the first stage of the study, and these results were validated in the second stage. The commonly used RGs ß-actin (ACTB) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were unstable according to all of the algorithms used. The findings were further validated via relative quantification of IL-5, CCL11, IFN-γ, and IL-17A using the stable and unstable RGs. The relative expression levels varied greatly according to normalization with the selected RGs. Appropriate selection of stable RGs will allow more accurate determination of target gene expression levels in patients with CRS.

Prognostic factors for recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyps.

OBJECTIVE: In this study, we aimed to clarify the prognostic factors affecting the ethmoid condition during a long-term follow-up after endoscopic sinus surgery in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: Thirty-six patients with CRSwNP underwent surgery from December 2008 to February 2012. All surgeries were performed by one surgeon, and all patients were followed up for at least 2 years postoperatively. We investigated the association of postoperative endoscopic findings with clinical parameters, mucosal eosinophil count and mRNA expression of CCL11, IL-5, and IFN-gamma in nasal polyps. RESULTS: Seventeen patients (47.2%) had severe mucosal edema, and the patency of each sinus was not confirmed during the >2-year follow-up. The mucosal eosinophil count and two eosinophil-associated factors, namely the CCL11 and IL-5 mRNA levels, were higher in the severe mucosal edema group than in the control group. The severe mucosal edema group was divided into two subgroups: the steroid-responsive and -resistant groups. Five patients (13.9%) had frank polyp formation because the oral steroids were less effective. The mucosal eosinophil count was significantly different among the four groups, including the control group (p=0.001); however, the CCL11, IL-5, and IFN-gamma mRNA levels were not significantly different. Although the IL-5 mRNA level was not significantly different among the four groups, it tended to increase when the sinus condition worsened. In the severe mucosal edema group, a higher IL-5 mRNA level was associated with earlier severe mucosal edema in the ethmoid cavity. CONCLUSION: The IL-5 mRNA level is associated with the time of severe edema formation in the ethmoid cavity. This finding permits early intervention on the postoperative course and would prevent polyp recurrence.

Adenoid cystic carcinoma of the larynx presenting with unusual subglottic mass: Case report.

A 33-year-old woman presented with an unusual subglottic bulging mass accompanied by prolonged cough and wheeze. Laryngeal endoscopy revealed a bilateral, symmetrical mass immediately below the vocal cords with marked airway obstruction. Chronic subglottic laryngitis with inflammation or another condition such as amyloidosis was initially suspected. Cervicothoracic computed tomography revealed an obvious reduction of laryngeal caliber caused by an engulfing mass extending from just under the vocal cords to the cricoid ring, which was associated with thyroid, arytenoid, and cricoid cartilage destruction. Histopathological diagnosis of a biopsy specimen collected via a tracheotomy revealed that the lesion was a cT4aN0M0 adenoid cystic carcinoma (ACC) originating from the laryngeal minor salivary glands. The patient was treated by total laryngectomy with elective bilateral neck dissection under general anesthesia. Gross inspection of resected tissue confirmed yellowish-white, solid tumor mainly circumferentially encompassing the lumina of the cricoid ring. The histopathological findings confirmed typical ACC accompanied by a predominant cribriform appearance with no evidence of lymph node metastasis. The patient remains well and free of recurrence or metastasis. We herein describe laryngeal ACC and discuss radiological images and the surgical pathology.

Acute exacerbation of Hashimoto thyroiditis mimicking anaplastic carcinoma of the thyroid: A complicated case.

The fibrous variant of Hashimoto thyroiditis is uncommon, accounting for approximately 10% of all cases of Hashimoto thyroiditis. We report a case of this variant that behaved like a malignant neoplasm. The patient was a 69-year-old man who presented with a right-sided anterior neck mass that had been rapidly growing for 2 weeks. Fine-needle aspiration cytology revealed clusters of large multinucleated cells suggestive of an anaplastic carcinoma. A week after presentation, we ruled out that possibility when the mass had shrunk slightly. Instead, we diagnosed the patient with an acute exacerbation of Hashimoto thyroiditis on the basis of laboratory findings. We performed a right thyroid lobectomy, including removal of the isthmus, to clarify the pathology and alleviate pressure symptoms. The final diagnosis was the fibrous variant of Hashimoto thyroiditis, with no evidence of malignant changes. Physicians should keep in mind that on rare occasions, Hashimoto thyroiditis mimics a malignant neoplasm.

Endoscopic modified medial maxillectomy for odontogenic cysts and tumours.

BACKGROUND: Odontogenic maxillary cysts and tumours originate from the tooth root and have traditionally been treated through an intraoral approach. Here, we report the efficacy and utility of endoscopic modified medial maxillectomy (EMMM) for the treatment of odontogenic maxillary cysts and a tumour. METHODOLOGY: We undertook EMMM under general anaesthesia in six patients: four had radicular cysts, one had a dentigerous cyst, and one had a keratocystic odontogenic tumour. RESULTS: The cysts and tumours were completely excised and the inferior turbinate and nasolacrimal duct were preserved in all patients. There were no peri- or postoperative complications, and no incidences of recurrence. CONCLUSION: Endoscopic modified medial maxillectomy appears to be an effective and safe technique for treating odontogenic cysts and tumours.

[A rare case of pharyngeal mesenchymoma demonstrating a variety of histopathological findings].

We encountered a 38-years-old female patient who was complaining of an unpleasant sensation of the left cervical area due to a recurrent tumor originating from the middle pharynx. She had a history of surgically resected neurofibroma and lipoma from the anterior oropharyngeal wall respectively 5 years and 11 years previously. The preoperative diagnosis of a benign, non-epithelial neoplasm was made based on the imaging studies and surgical treatment was scheduled. An extended surgical resection of the middle pharynx including normal mucosa and a part of the tongue base was successfully accomplished. To cover the pharyngeal defect, a right antero-lateral thigh musculo-cutaneous flap was used for reconstruction. Microscopically, the surgically resected tissue showed a mixed condition of mature cartilaginous, bony and fibroadipose tissue without atypia. The final diagnosis was a benign mesenchymoma which was thought to have developed from pluripotential mesenchymal cells. We considered that the past tumorous lesions had possibly originated in those cells. Because pluripotential mesenchymal cells cannot easily be identified with ordinary histopathological examination, the determination of optimal surgical margins is difficult. In the case of mesenchymoma, substantial marginal tissue should be resected in order to prevent recurrence even in the case of a pathologically-proven benign tumor.

Endoscopic single-handed septoplasty with batten graft for caudal septum deviation.

OBJECTIVE: Septoplasty is usually performed with a Killian incision in Japan. However, the major drawback of the Killian incision is the inability to correct deviations of the caudal part of the septum. For patients with mild deviation of the caudal part of the septum but with a straight caudal end, we performed a modified Killian incision and used a batten graft to correct the deviated cartilage under endoscopy. The aim of this study was to evaluate the usefulness of our surgical technique for these cases. METHODS: We prospectively collected data of 17 patients who underwent endoscopic septoplasty with a batten graft. Objective assessment by computed tomography and subjective assessment by questionnaire were performed before and 3 months after the surgery. RESULTS: On computed tomography, the ratio of the area of the convex side to that of the concave side in the anterior portion of the nasal cavity was significantly improved after surgery (p<0.001). Subjective assessment revealed a significant improvement in nasal obstruction (p=0.002). There were no complications in this study. CONCLUSION: The herein-described septoplasty with a batten graft is technically easy and considered to be useful for deviation of the caudal part of the septum in selected cases.